The growing burden of non-communicable diseases amidst the largest burden of HIV in South Africa leads to disease combinations of multimorbidity with the complexity of care. We conducted a cross-sectional study to assess multimorbidity, medication adherence, and associated factors among out-patients with chronic diseases in primary health care (PHC) facilities in Tshwane, South Africa. A structured questionnaire was used to collect data on comorbidities and medication adherence, along with socio-demographic and lifestyle factors. Logistic regression models were used to analyse the determinants of multimorbidity and medication adherence. In all 400 patients with chronic diseases (mean age: 47 ± 12 years) living in poor environments, common chronic conditions were hypertension (62%), diabetes (45%), HIV (44%), TB (33%), hypercholesterolemia (18%), and gout (13%). The proportion of concordant comorbidity (i.e., diseases with similar risk profiles and management) was 72%, more than 28% of discordant comorbidity (i.e., diseases not related in pathogenesis or management). Most patients had two coexisting chronic conditions (75%), while few had more than two chronic conditions (23%) and single-occurring conditions (2%). Prevalence rates for common multimorbidity patterns were 25% (HIV and TB), 17% (hypertension and diabetes), 9% (hypertension, diabetes, and hypercholesterolemia), and 2% (hypertension diabetes and HIV), while medication adherence was estimated at 74%. In multivariate analysis, multimorbidity was associated with an older age and lower socio-economic status, while medication non-adherence was associated with a younger age and socio-economic factors. The study highlights the presence of multimorbidity among primary care patients attributed to hypertension, diabetes, HIV, and TB in South Africa with non-adherence to medication in one-third of patients. Policies are needed for education on multimorbidity with a need to optimize lifestyle modifications, perhaps proactive outreach or nursing contact with high-risk patients with public-health-sensitive conditions, such as HIV and/or TB, as well as patients with a history of non-adherence to medications. Considerations should be given to the development of a medication adherence scale for multiple chronic conditions beyond assessing adherence to a single index medication.