The WHO Model List of Essential Medicines (MLEM) has since 1977 helped prioritize and ensure availability of medicines especially in low- and middle-income countries. The MLEM consists mainly of generic medicines, though recent trends point towards listing expensive on-patent medicines and increasing global support for medicines against non-communicable diseases. However, the implications of such changes for national essential medicines list (NEML) updates for access to essential medicines has received relatively little attention. This study examined how government agencies and other actors in Kenya, Uganda and Tanzania participate in and influence the NEML update process and subsequent availability of prioritized medicines; and the alignment of these processes to WHO guidance. A mixed study design was used, with qualitative documentary review, key informant interviews and thematic data analysis. Results show that NEML updating processes were similar amongst the three countries and aligned to WHO guidelines, albeit conducted irregularly, with tendency to reprioritization during procurement stages, and were not always accompanied by revision of clinical guidelines. Variations were noted in the inclusion of medicines against cancer and hepatitis C, and the utilization of health technology assessment (HTA). For medicines against diseases with high global engagement, such as HIV/AIDS and TB, national stakeholders had more limited inputs in prioritization and funding. Furthermore, national actors were not influenced by the pharmaceutical industry during the NEML update process, nor were any conflicting agendas identified between health, trade and industrial policies. Hence, the study suggests that more attention should be paid to the combination of HTAs and NEMLs, particularly as countries work towards universal health coverage, in addition to heightened awareness of how global disease-specific initiatives may confound national implementation of the NEML. The study concludes with a call to strengthen country-level policy and procedural coherence around the process of prioritizing and ensuring availability of essential medicines.