BackgroundProblem based learning is being highly implemented in many medical schools worldwide due to its perceived advantages including improvement of problem-solving abilities, development of communication skills, creation and development of critical thinking skill, and making of individuals to be lifelong learners & responsible for their own learning process.ObjectiveThe study aimed to compare academic satisfaction of Problem and Lecture based learning of regular undergraduate health science students in Ethiopian Universities, 2021.MethodInstitution based comparative cross sectional study was conducted from February 1–30, 2021. Data were collected using a pretested structured and self-administered questionnaire among 850 eligible students from two Universities. Data were entered into EPI info version 6.04 and analyzed using SPSS version 23. Binary Logistic regression model was fitted to identify factors associated with academic satisfaction considering the association to be significant p- value < 0.05.ResultThe study result revealed that the magnitude of academic satisfaction among problem based and lecture based learning students were 50.9 and 49.9% respectively. Similarly, problem based learning students were more likely to be academically satisfied than lecture based learning students in their type of curriculum with (AOR = 1.50, 95% CI = 1.02, 2.21). Experience of classroom distress (AOR = 1.93, 95% CI = 1.22, 3.06), quality of teaching (AOR = 0.54, 95% CI = 0.34, 0.86), relationship with classmates (AOR = 0.33, 95% CI = 0.13, 0.80), course content (AOR = 0.56, 95% CI = 0.33, 0.93) and accessibility of technology in the campus (AOR = 0.62, 95% CI = 0.40, 0.96) were the significant factors of academic satisfaction of problem based learning students. Year of study (AOR = 0.29, 95% CI = 0.17, 0.48), quality of teaching (AOR = 0.51, 95% CI = 0.31, 0.85), course content (AOR = 0.59, 95% CI = 0.35, 0.97) and energy & effort (AOR = 0.55, 95% CI = 0.35, 0.88) were significantly associated with academic satisfaction among lecture based learning students.ConclusionThe study revealed that the academic satisfaction among problem based learning students was higher than lecture based learning students. Incorporating and implementing problem based learning as a formal instructional method in across the universities curriculum is recommended.