Malaria is a complex disease and main community health problem in Africa and the top leading cause of outpatient visits, admissions, and deaths in Ethiopia. Its effective management is possible through early diagnosis and immediate treatment employing antimalarials. The quality of these drugs has to be good enough to attain their intended purpose. However, there are treatment failures resulted from the consumption of falsified and substandard antimalarials. Therefore, the current study was undertaken to evaluate the quality of two commonly used antimalarial drugs [chloroquine phosphate and quinine sulfate tablets] and to determine whether the quality of these drugs was affected by the origin, brand and sample collection sites in South-West Ethiopia.Random sampling based on Ethiopian malaria eco-epidemiological strata map, with different levels of medicines outlets, was applied to select sampling sites.Sixty samples were bought from 43 drug retails (pharmacy, drug store, and drug vendor) in twelve different geographical locations of South-West Ethiopia between June and July 2016. Visual inspection was done for all samples before the lab experiment. A 28.3%, 31.7%, and 6.8% of samples failed to comply with the Pharmacopoeial quality standards for visual inspection, hardness and weight variation tests, respectively. Statistical analysis revealed that origin and geography from which samples were collected significantly affects the active pharmaceutical content of both drugs at < 0.05 level. Significant variation was observed for chloroquine samples within batches of the same manufacturing and between origins.This study indicated that all the chloroquine and quinine tablets met the quality specification concerning friability, dissolution and assay. Out-of-specification results for weight variation, hardness and visual inspection tests for the chloroquine tablets are signs of substandard/spurious/falsely labeled/falsified/counterfeit actions that may compromise the quality of these drugs. Besides, within the acceptance limit, the origin of drugs and collection sites have found to determine the quality which raises good manufacturing practice and storage (drug supply chain system) issues to be evaluated.