The emergence of drug-resistant tuberculosis (DR-TB) is becoming a challenge to the national TB control programs including Ethiopia. Different risk factors are associated with the emergence of DR-TB. Identifying these risk factors in a local setting is important to strengthen the effort to prevent and control DR-TB. Thus, this study aimed to assess the risk factors associated with drug-resistant TB in Ethiopia. The Preferred Reporting Items for Systematic Reviews and Meta-analysis checklist was followed to conduct this study. We systematically searched the articles from electronic databases and gray literature sources. We used the Joanna Briggs Institute Critical Appraisal tools to assess the quality of studies. Data were analyzed using STATA version 15. We estimated the pooled OR along with 95%CI for each risk factor. The heterogeneity of the studies was assessed using the forest plot and I ² heterogeneity test. Besides, we explored the presence of publication bias through visual inspection of the funnel plot and Egger’s regression test. After intense searching, we found 2238 articles, and 27 eligible studies were included in the final analysis. Based on the pooled analysis of the odds ratio, unemployment (OR; 2.71, 95% CI; 1.64, 3.78), having a history of the previous TB (OR; 4.83, 95% CI; 3.02, 6.64), having contact with a known TB patient (OR; 1.72, 95% CI; 1.05, 2.40), having contact with a known MDR-TB patient (OR; 2.54, 95% CI; 1.46, 3.63), and having pulmonary TB (OR; 1.80, 95% CI; 1.14, 2.45) were found to be the risk factors of drug-resistant TB. While older age TB patients (OR; 0.77, 95% CI; 0.60, 0.95) including age above 45 years OR; (0.76, 95% CI; 0.55, 0.97), and males (OR; 0.86, 95% CI; 0.76, 0.97) were found to had lower risk of DR-TB compared to their counterparts. A previous history of TB treatment is a major risk factor for acquiring DR-TB in Ethiopia that might be due to poor adherence during the first-line anti TB treatment. Besides, having contact with a known TB patient, having contact with a known MDR-TB patient, having pulmonary TB, and being unemployed were the risk factors of DR-TB in Ethiopia. Thus, active screening of TB contacts for DR-TB might help to detect DR-TB cases as early as possible and could help to mitigate its further transmission across the community.