Assessing underlying illnesses can inform health stakeholders about chronic conditions for targeted enhanced prevention and treatment strategies. Since the Eastern Cape Province has a high disease burden, this study aimed to assess the prevalence of human immunodeficiency virus (HIV) infection and selected disease burden of outpatients from primary health care (PHC) facilities in the districts. From February 2019 to February 2021, a cross-sectional study was conducted. Research Electronic Data Capture (REDCap)-enabled tablets were used to collect data from consenting outpatients over the age of 18 years using an interviewer-administered WHO core and expanded stepwise questionnaire. The statistical analysis was mainly descriptive with the use of counts, frequencies, and summary measures. The study population was predominantly female (86.5%). Prevalent diseases included HIV, hepatitis B virus (HBV) infection, and cardiometabolic diseases. HIV prevalence was 52% and highest in the age group of 30–59 years. In people living with HIV, the nonsuppressed viral load (VL 1000 copies/mL) was highest in the age group of 40–49 years (34.6%). Prevalence of diabetes was highest at the Mhlontlo subdistrict (42.3%), while the King Sabata Dalindyebo (KSD) subdistrict had the highest prevalence of HBV infections (39.1%). Based on the findings, we advocate for intermittent assessments of disease burden in certain settings, such as rural areas, to improve PHC practice and outcomes, especially in the wake of the coronavirus disease (COVID-19) pandemic.