Drug shops are the first point of care for most community members in low-resource countries. Because of symptomatic similarities with common illnesses such as malaria, probable coronavirus disease 2019 (COVID-19) cases may seek care at drug shops, where the knowledge and skills required to handle it may be lacking, thereby fostering community spread of the disease. This single-arm study provided an intervention to improve COVID-19-related knowledge, attitude, and practices of patent medicine vendors (PMVs) in 97 participating drug shops selected through cluster sampling in Owerri, southeastern Nigeria. The intervention involved a drug shop sensitization using information, education, and communication material, as well as training on the use of a risk assessment checklist to identify probable COVID-19 cases and to take appropriate action. Data were collected to determine the effect of this intervention using a pre-tested questionnaire and practice observation checklist, first at baseline and then 3 months post-intervention. Data analysis involved exploratory analysis and the t-test to determine pre- and post-intervention mean score differences at the 5% α level. There was post-intervention knowledge improvement on the COVID-19 causative pathogen (98.1% post-intervention versus 61.9% pre-intervention) and disease transmissibility from person to person (95.9% post-intervention versus 81.4% pre-intervention) among other knowledge domains. There was significant post-intervention improvement for positive attitude, with a mean gain score of 2.8 ± 1.7 (t = 4.4, P = 0.005), and preventive practices, with a mean gain score of 6.0 ± 4.7 (t = 4.1, P = 0.007). Engaging patent medicine vendors in the pandemic response plans through targeted interventions such as drug shop intervention could prove vital in the fight against COVID-19.