PURPOSE: Clinician burnout is a health care crisis, especially for medical trainees, with few evidence-based curricula on durable resiliency skills. The researchers hypothesize that a curriculum fostering uncertainty tolerance, self-compassion, and adaptive thinking can enhance medical students' resilience. Applied improvisation, derived from the principles of unscripted, collaborative theater, has been used to strengthen clinicians' interpersonal and communication skills. This study investigates the potential impact of improvisation-based training on medical students' capacity to tolerate uncertainty, cultivate self-awareness, and build resilience. METHOD: All first-year medical students at The University of Arizona College of Medicine-Phoenix attended four 3-hour mandatory applied improvisation training sessions during 15 months (2022-2024). A mixed-methods approach was used to expand knowledge of the educational process, content, and impacts. Quantitative data included 3 validated scales: Intolerance of Uncertainty Scale 12 (IUS-12), Self-Compassion Scale (SCS), and the Connor-Davidson Resilience Scale (CD-RISC). Qualitative data included brief text responses to a set of question prompts, anonymous feedback collected in the live postsession debrief, and a reflective writing assignment analyzed for key themes and various aspects of the improvisational training. RESULTS: Of the 118 students, 108 (92%) consented to participate in this study, and 84 (76%) completed all quantitative and qualitative instruments. The quantitative data showed statistically significant improvement in the SCS over time (mean [95% CI] change in score from session 1: -0.01 [-0.11 to 0.09] for session 2, 0.05 [-0.05 to 0.15] for session 3, and 0.12 [0.02-0.22] for session 4; P = .04), with no significant improvement on the IUS-12 or CD-RISC. The qualitative data indicated that most participants experienced an overall positive impact, with a few reporting disliking the content and nature of improvisation training. CONCLUSIONS: These findings carry potential implications for curricular design in filling a crucial gap of teaching uncertainty tolerance, self-compassion, and resiliency to medical students.