Background. In Ethiopia since 2012, the Ethiopian Federal Ministry of Health and Education implemented a new medical education initiative in 13 institutions. Currently, as a nation, very little is known about the predictors of academic performance for new medical education curriculum-based students. Identifying different factors affecting students’ academic performance in the local context so as to enrich the empirical evidence and provide new insights into the effect of variables in developing countries is very important. Thus, the main aim of this study was to assess predictors of academic performance for new medical education initiative curriculum-based medical students. Objective. This study designed to assess the predictors of academic performance for new medical education initiative curriculum-based medical students found in Southern Nations and Nationalities Peoples’ Region, Ethiopia. Methods. Institutional-based cross-sectional study design was used on 472 new medical education system students. The study setting includes three medical institutions (Dilla University College of Medicine and Health Science, Wolaita Sodo University College of Medicine and Health Sciences, and Yirgalem Hospital Medical College) within southern region from February to July 2020. The study subjects were those medical students under the NMEI curriculum and had at least one-year cumulative grade point average in the abovementioned institutions. Results. A total of 167 (35.4%) of the students’ academic performance scores were poor. Being agriculture graduate with educational background, mothers with no formal education, being married, first-degree performance score of 2.7–3.2 CGPA, monthly allowance of 10–24.99 USD, nondormitory, student age of 31–35 years old, and being stressed have shown an association with poor academic performance score of the students. Conclusion. First-degree educational background, marital status, maternal educational status, first-degree academic performance, age of the student, monthly allowance, residency during medical school, and history of stress were significant predictors of academic performance for new medical education system students. Thus, it is recommended that special attention should be paid to the admission criteria and financial support of the students.