Background Breast cancer is the leading cause of cancer death worldwide and the second most common cancer overall. Breast self-examination is one of the cheapest methods used for the early detection of breast cancer in asymptomatic women. However, in Ethiopia, most of the breast self-examination studies were not conducted among women in the general population. Therefore, this study aimed to assess breast self-examination practice and associated factors among women of reproductive age in the North Shewa Zone, Oromia. Method A community-based cross-sectional study was conducted in the North Shewa zone from May 18/2022 to June 18/2022. 1076 women of reproductive age were selected by simple random sampling. For the quantitative part of the study, an interviewer-administered questionnaire was used, and focus group discussions were used for the qualitative part. SPSS version 26 was used for the analysis. Variables with a P-value < 0.25 in the bivariable analysis were included in the multivariable logistic regression model. The degree of the association was expressed using an adjusted odds ratio (AOR) with a 95% confidence interval (CI) at a P-value < 0.05. Results Overall 192(18.2%) with 95% CI (15.7, 20.5) of the participants had ever performed BSE. Among these, only 20 (10.4%) had practiced monthly. Being younger-aged women (15–24) [AOR = 3.9, 95% CI (2.2–6.8)], having a family history of BC [AOR = 6.9, 95% CI (4.6–10.3)], being knowledgeable on BSE [AOR = 3, 95% CI (1.9–4.3)], having high perceived susceptibility [AOR = 1.7, 95% CI (1.2–2.5)], having high self-efficacy [AOR = 1.5, 95% CI (1.1–2.3)] and having a high perceived benefit to BSE [AOR = 1.5, 95% CI (1.1–2.3)] were factors significantly associated of BSE practice. Conclusion BSE practice in the North Shewa zone was very low. Age, family history of BC, knowledge of BSE practice, perceived susceptibility, benefit, and self-efficacy were independent predictors of BSE practice. North Shewa Zonal Health Office and other stakeholders should disseminate teaching materials that address the benefit of BSE practice.