ABASTRACT Objective This study aims to assess the impact of LearnGuide, a specialized ChatGPT tool designed to support self-directed learning among medical students. Materials and methods In this 14-week randomized controlled trial (ClinicalTrials.gov NCT06276049), 103 medical students were assigned to either an intervention group, which received 12 weeks of problem-based training with LearnGuide support, or a control group, which received identical training without AI assistance. Primary and secondary outcomes, including Self-Directed Learning Scale scores at 6 and 12 weeks, Cornell Critical Thinking Test Level Z scores, and Global Flow Scores, were evaluated with a 14-week follow-up. Mann-Whitney U tests were used for statistical comparisons between the groups. Results At 6 weeks, the intervention group showed a marginally higher median Self-Directed Learning Scale score, which further improved by 12 weeks (4.15 [95% CI, 0.82 to 7.48]; p = 0.01) and was sustained at the 14-week follow-up. Additionally, this group demonstrated notable improvements in the Cornell Critical Thinking Test Score at 12 weeks (7.11 [95% CI, 4.50 to 9.72]; p < 0.001), which persisted into the 14-week follow-up. The group also experienced enhancements in the Global Flow Score from 6 weeks, maintaining superiority over the control group through 12 weeks. Conclusions LearnGuide significantly enhanced self-directed learning, critical thinking, and flow experiences in medical students, highlighting the crucial role of AI tools in advancing medical education.