Self-medication is identified by the consumption of medications without a prescription or guidance from a qualified prescribing professional. This study estimated the prevalence, profile, and associated factors with self-medication during the COVID-19 pandemic in Brazil. A cross-sectional study was conducted through a household survey in the Alegre city, from November to December 2021. Descriptive analysis was performed for the sociodemographic and clinical characteristics of the interviewees. Poisson regression with robust variance was used to identify the association of sociodemographic and clinical variables with self-medication. A total of 654 people were interviewed, of whom 69.4% were self-medicating. The younger age group (PR = 1.13; 95% CI = 1.01–1.26), female gender (PR = 1.19; 95% CI = 1.04–1.37), consumption of alcoholic beverages (PR = 1.13; 95% CI = 1.01–1.25), and problems with adherence to pharmacological treatment (PR = 1.15; 95% CI = 1.04–1.28) were associated with self-medication, while the occurrence of polypharmacy (PR = 0.80; 95% CI = 0.68–0.95) was a protective factor for self-medication. Self-medication was directly related to over-the-counter drugs, with analgesics dipyrone and paracetamol being the most commonly used. Self-medication consumption of prescription drugs, including those under special control, was identified to a lesser extent.