Objective To assess student learning patterns, performance, and long-term knowledge retention comparing team-based learning (TBL) versus didactic lecture. Methods Students were recruited from the Therapeutics 6 course. Primary end points include the following: time spent learning content for each topic, student performance on course examinations, and student performance on follow-up examination five months after course completion. Results Students (n = 35) spent more time learning topics taught using TBL (mean = 21.12 ± 11.02 hours) compared to didactic lecture (mean = 17.54 ± 7.78 hours) (p = 0.002). There was no significant difference in mean score on course examinations (TBL mean = 81.84 ± 8.19; didactic lecture mean = 80.50 ± 7.10; p = 0.369) or on the follow-up examination (TBL mean = 63.65 ± 10.14; didactic lecture mean = 65.43 ± 10.11; p = 0.419). Conclusions Although students used more time learning content for topics taught using TBL compared to those presented by didactic lecture, immediate and long-term exam performances were not significantly different. Educators using TBL should design learning experiences to develop skills that can be strengthened by TBL, including communication, professionalism, team work, and critical thinking. Student preparation time should be considered when implementing TBL within a course or curriculum.