Objectives: This study aimed at assessing the prevalence of antibiotics non-adherence and its associated factor among households in southern Ethiopia. Methods: A community-based cross-sectional study was conducted among 323 randomly selected households in Wenago town. To collect the data, structured questionnaire was used. Categorical variables were represented by frequency and percentage. For continuous variables, the mean value and standard deviation were used. Bivariate and multivariate logistic regression analyses were used to identify factors related to antibiotic non-adherence. Finally, for significant factors with p-values less than 0.05, the adjusted odds ratio with 95% confidence interval was calculated and evaluated. Results: The prevalence of antibiotic non-adherence in the household was 194 (60.1%) (95% confidence interval = 55.1–65.6). Remission of symptoms (63%) is one of the top reasons for antibiotic non-adherence in the home. Male sex (adjusted odds ratio = 1.77, 95% confidence interval = 1.03–3.08), lower educational status (adjusted odds ratio = 3.42, 95% confidence interval = 1.51–7.75; adjusted odds ratio = 2.37, confidence interval = 1.12–5.02), poor attitude toward antibiotics use (adjusted odds ratio = 1.89; 95% confidence interval = 1.23–3.04), poor knowledge about antibiotics use (adjusted odds ratio = 1.34; 95% confidence interval = 1.11–2.39), and no-prescription information from pharmacy (adjusted odds ratio = 2.02, 95% confidence interval = 1.09–3.72) were all associated with non-adherence. While no medication discomfort (adjusted odds ratio = 0.31, 95% confidence interval = 0.178–0.56) had a negative effect on non-adherence. Conclusion: In this study, antibiotic non-adherence was considerably high among the participants. Being male, lower educational status, poor attitude, poor knowledge, no-prescription information from pharmacy/druggist, and medication discomfort were related with antibiotic non-adherence. As a result, community service providers must provide relevant prescription information as well as appropriate counseling to antibiotic non-adherent patients.