Stanislav Dmitrievich Poletaev was appointed as the first Rector of the Tselinograd State Medical Institute (1964–1970). Medical Universities from across the Soviet Union supported the development of the Institute by providing personnel, equipment, academic and scientific literature. Stanislav Dmitrievich Poletaev, a Doctor of Medical Sciences and Professor, made significant efforts in establishing the departments and recruiting the teaching staff. In 1964, the Institute admitted 300 students to the first year and 100 students to the second year of the General Medicine program. Between 1964 and 1969, all 35 key departments essential for comprehensive medical education were established, and a dormitory building on Pushkin Street was constructed. In 1965, the Ministry of Healthcare of the Kazakh SSR approved the first composition of the Institute's Board of Academics, consisting of 17 members. In a short period, the TSMI became one of the prominent and respected higher education institutions in Kazakhstan.

From 1978 to 1997, the University was led by prominent scientist-pathophysiologist Valentin Gavrilovich Korpachev, Doctor of Medical Sciences and Professor. During these years, the Pediatric and Medical-Biological faculties were established, along with a Faculty for Training Mid-Level Medical Professionals. For the first time, disciplines began to be taught in the State Language at the University, and collaboration with Practical Healthcare was enhanced. Special attention was paid to student moral and ideological education. A health and wellness center operated year-round in the dormitories. Student Interest Clubs were organized and successfully operated. In 1990, the Central Research Laboratory was established, and an eight-story academic building along with a communal dormitory were built. In 1992, a dissertation council was established for defending candidate dissertations in Pathological Physiology and the number of doctors and candidates of sciences among the University faculty increased. Among 250 teachers, there were 19 doctors and 131 candidates of medical sciences.

From 1997 to 2001, the Akmola State Medical Academy was headed by Rais Kazhkenovich Tulebaev, Doctor of Medical Sciences, Professor, academician of the National Academy of Sciences of Kazakhstan, full member of several international academies, honored worker of Kazakhstan, and a renowned scientist in otorhinolaryngology and occupational diseases. In 1997, the status of the University was elevated. By the Resolution of the Government of Kazakhstan No. 263 dated February 25, 1997, the TSMI was transformed into the Akmola State Medical Academy (ASMA). During this time, 3 dissertation councils were opened for defending doctoral dissertations in Surgery, Traumatology and Ear, Nose, and Throat Diseases. Tulebaev initiated opening of 10 branches of research institutes and centers were opened, including branches of the National Surgery Center, the National Center for Maternal and Child Health, the National Center for Urology, the National Center for Pediatrics and Pediatric Diseases, the National Center for Healthy Lifestyle, and others.  A new faculty of medical biology was opened, and for the first time, national-level journals Astana Medical Journal and Valeology were published.

From 2001 to 2004, the academy was headed by Polat Kazymbet, Doctor of Medical Sciences, Professor, Vice-President of the Azat Association for Radiation Research, full member of the New York Academy of Sciences, and academician of the Academy of Pedagogical Sciences of Kazakhstan. In 2003, the Academy was renamed into the Kazakh State Medical Academy by the Resolution of the Government of Kazakhstan on March 14, 2003. Under Polat Kazymbetovich’s leadership, several new faculties were opened, including the faculty of pharmacy, dentistry, oriental medicine, the faculty for mid-level medical workers, and the faculty for continuous professional development. Dissertation councils for defending dissertations in Microbiology and Forensic Medicine were established. He also initiated and oversaw the construction of the main building of the Astana Medical University and the establishment of the Institute of Radiobiology and Radiation Protection in 2004.

From 2004 to 2007, the Academy was led by Doskaliyev Zhaksylyk Akmurzayevich, Doctor of Medical Sciences, Professor, and Academician of the Academy of Medical Sciences of the Republic of Kazakhstan, as well as a recipient of the State Prize of the Republic of Kazakhstan. During his tenure, he established the Educational and Methodological Association (EMA) for medical universities in Kazakhstan, oversaw the construction and commissioning of a new administrative and academic building, continued the work of enhancing the educational process, established a computer center, developed and introduced a new nationwide educational standard, and founded the Department for the Development of the State Language. Additionally, a scientific-practical journal, Otorhinolaryngology, was launched. During these years, the Academy employed 56 doctors and over 150 candidates of science.

In 2007-2008, the position of Rector of Kazakh State Medical Academy was held by Timur Salavatovich Tapbergenov, Doctor of Medical Sciences and Professor. Under his leadership, efforts were focused on the integration of innovative teaching technologies into the educational process. On May 13, 2008, by the Resolution of the Government of the Republic of Kazakhstan No. 451, the Academy was reorganized into the Joint-Stock Company Kazakh Medical Academy, with 100% state participation in its authorized capital.

From 2008 to 2010, Zhaksybai Shaimardanovich Zhumadilov, Doctor of Medical Sciences, Professor, Honored Worker of Kazakhstan, and Laureate of the State Prize of Kazakhstan named after Al-Farabi and the International Prize "Altyn Adam" led the JSC Kazakh Medical Academy. On January 6, 2009 (by Decree No. 81), the institution was transformed into the Joint-Stock Company Astana Medical University and joined the National Medical Holding. The regulatory framework for the university's operation as a joint-stock company and member of the Holding was developed, and the organizational structure was reformed. For the first time, a Master of Business Administration (MBA) program was introduced in partnership with Parkway College (Singapore), Columbia University (New York, USA), and Danube University (Vienna, Austria). A strategic development plan for 2010-2014 was designed, and the Department for the Development of the State Language and Language Policy was organized. Education in English was initiated, and partnerships were formed with leading universities in Austria, Japan, Singapore, Iran, the USA, and Russia. The Republican Center for Innovative Medical Education and Science Technologies was established, and two dissertation councils for the defense of doctoral theses in seven specialties were created. During this period, the university employed 51 doctors, over 180 candidates of science, 33 professors, and 69 associate professors

From 2010 to 2019, the university was led by Mazhit Zeynullovich Shaidarov, a graduate of this institution, Doctor of Medical Sciences, professor, academician of the National Academy of Sciences of the Republic of Kazakhstan, the Academy of Pedagogical Sciences of Kazakhstan, and the European Academy of Natural Sciences, as well as an honored figure of Kazakhstan.  During his tenure, significant achievements were made in modernizing medical education and expanding international relations. Agreements were signed with 80 foreign universities and organizations from the USA, Europe, and Asia, and for the first time, students from India and Pakistan were admitted to the university. Faculty and students were given opportunities for academic exchanges with medical universities in Belgium, Greece, Spain, Norway, and South Korea. In 2011, Astana Medical University ranked first among medical universities in the National General Ranking. Following the implementation of the EFQM quality management system, the university received a "Recognized Excellence" certificate, earning 5 stars. At the initiative of the rector and under his direct leadership, a museum was established at the National Medical University of Astana.

From 2019 to 2021, the university was led by Professor Dainius Pavalkis, a member of the European Commission's Health Research Group and the European Group of Experts on Research, Innovation, and Scientific Policy. During his time, the university was a leader in transitioning to a multi-tiered higher education system, being the first medical university in Kazakhstan to begin multi-level training of medical and scientific-pedagogical staff. The Academic Council was restructured into the University Senate, consisting of 41 members. Since 2011, as part of the Bologna Process, the university has actively practiced international academic mobility, entering into memorandums of cooperation with medical universities from both near and far abroad. Over 6,000 students were enrolled during this period, and 812 full-time faculty members, including 92 doctors, 211 candidates of science, 27 PhDs, 50 professors, and 87 associate professors, were employed.

Since 2021, the Astana Medical University NCJSC has been led by PhD Kamalzhan Talgatovich Nadyrov, a graduate of S.D. Asfendiyarov Kazakh State University, Turan University, and the Higher School of Public Health, holder of an MBA in Public Health and an Executive MBA in Business Administration. Under the leadership of Kamalzhan Talgatovich, a new Strategic Development Plan for the Medical University of Astana for 2022-2026 was developed and implemented. As part of this plan, the University began its transformation into a Research Institution and carried out several significant initiatives. These included the opening of the Preventive Medicine Research Institute named after Academician Y.D. Dalenov and the Radiology Research Institute named after Academician Z.K. Khambazbaev, the Healthcare Academy and the AMU Development Endowment Fund, along with the modernization of the University's simulation center. Other key activities during this period included organizing student initiation ceremonies and graduation events at Astana Opera in a new format, establishing a commercialization office, holding the "Young Scientist" forum, and creating the University Museum's Scientific and Methodological Council. The University also signed important agreements, such as memorandums with the multinational company Yandex Cloud Kazakhstan for the development of digital healthcare technologies, Astana Hub and Association for the Development of Artificial Intelligence, Istanbul Medipol University for strategic partnerships, and the Ministry of Science and Higher Education of the Russian Federation.