Over-the-counter antibiotic access is common in low-and-middle-income countries and this may accelerate antimicrobial resistance. Our study explores critical aspects of the drug seller–client interaction and antibiotic dispensing patterns for simulated COVID-19 symptoms during the pandemic in two study sites in Tanzania and Uganda, countries with different government responses to the pandemic. Research assistants posing as clients approached different types of drug sellers such as pharmacies (Pharms), drug shops (DSs), and accredited drug dispensing outlets (ADDOs) in Mwanza, Tanzania (nPharms = 415, nADDOs = 116) and Mbarara, Uganda (nPharms = 440, nDSs = 67), from June 10 to July 30, 2021. The mystery clients held no prescription and sought advice for simulated COVID-19 symptoms from the drug sellers. They documented the quality of their interaction with sellers and the type of drugs dispensed. Adherence to COVID-19 preventive measures and vigilance to COVID-19 symptoms was low in both sites but significantly higher in Uganda than in Tanzania. A higher percentage of drug sellers in Mbarara (Pharms = 36%, DSs = 35%, P-value = 0.947) compared to Mwanza (Pharms = 9%, ADDOs = 4%, P-value = 0.112) identified the client’s symptoms as possibly COVID-19. More than three-quarters of drug sellers that sold prescription-only medicines in both Mbarara (Pharms = 86%, DSs = 89%) and Mwanza (Pharms = 93%, ADDOs = 97%) did not ask the MCs for a prescription. A relatively high percentage of drug sellers that sold prescription-only medicines in Mwanza (Pharms = 51 …