Background: Lack of access to essential medicines is one of the most important public health problems in Ethiopia. The objective of this study was to verify availability, affordability and prices of essential medicines in primary health care units and private medicine outlets of South Wollo Zone. Methods: A facility-based cross-sectional study was undertaken in 10 primary health care units and 10 private medicine outlets. Data were collected through patient exit interview, record review, observation and interview of relevant bodies. Medicines prices were compared with international reference prices to obtain a median price ratio. The daily wage of the lowest paid government worker had been used to measure medicines affordability. Chi-square test and their p-values at the level of significance of 5% were used to define statistical associations. Odds ratios and their 95% confidence interval were used to look into the strength of association. Results: Average availability of essential medicines in primary health care units and private medicine outlets was 85.5% and 91.1% respectively. Based on prescriptions filled, 94% of the patients left the facility with all the prescribed medicines. The median price ratio of lowest price generics was 0.92, 1.25 and 1.76 times the international reference price for public procurement price, public sector dispensing price and private sector retail price, respectively. Among the total respondents that sought treatment, 56% incurred costs of more than 12.65 Birr on medicines. Conclusion: The survey revealed efficient public procurement price, acceptable retail price and higher availability in both the public and private sectors; however medicines were less affordable in both sectors. Different financing options could improve the affordability of essential medicines for low-income population.