Context Bedside clinical teaching is the backbone of clerkship education. Data-driven methods for supplementing bedside encounters with standardized content from vetted resources are needed. Objective To compare a flipped-classroom versus an interactive online-only instruction for improving knowledge, skills, self-directed learning (SDL) behaviors, and satisfaction in a medical school clerkship. Methods An IRB-approved prospective study employing a peer-reviewed clinical reasoning curriculum in neurology was conducted; 2nd-4th year medical students rotating through a required clerkship were enrolled. Students were randomized to flipped-classroom (i.e., flipped) or interactive asynchronous online instruction (i.e., online-only), which supplemented existing bedside teaching. Baseline and end-of-course knowledge, skill development, SDL behaviors, satisfaction, and long-term retention were assessed by peer-reviewed clinical reasoning exam, NBME scores, faculty/resident clinical evaluations, non-compulsory assignment completion, end-of-clerkship surveys, and objective structured clinical exam (OSCE). Results 104 students (49 flipped, 55 online-only) were enrolled. Age, gender, and training level did not differ by group (all p > 0.43); baseline knowledge was higher in the flipped group (p = 0.003). Knowledge-based exam scores did not differ by group even after adjusting for differences in baseline knowledge (2.3-points higher in flipped group, 95%CI -0.4-4.8, p = 0.07). Clinical skills were significantly higher in the flipped group, including examination skills (4.2 +/- 0.5 vs. 3.9 +/- 0.7, p = 0.03) and future housestaff potential (4.8 +/- 0.3 vs 4.5 +/- 0.6, p = 0.03). Students in the online-only group were more likely to engage in SDL (42 vs. 12%, p = 0.001) and reported more hours studying (6.1 vs. 3.8 hours, p = 0.03). Satisfaction (p = 0.51) and OSCE scores (p = 0.28) were not different by group. Conclusions In this comparative study of two evidence-based curricular delivery approaches, we observed no difference in knowledge acquired. Greater clinical skills were observed with flipped instruction, while more SDL was observed with online-only instruction. Supplementing bedside teaching with blended instruction that balances live skill development with vetted online resources is optimal for clerkship education.