Background <p>Anatomy is a fundamental cornerstone of medical education and plays a critical role in clinical success. Nevertheless, many students perceive it as a content-heavy and challenging subject. This highlights the need for innovative teaching approaches that foster deeper understanding, strengthen connections to clinical applications, and promote active student engagement. One such approach is graphic medicine, a branch of comics and healthcare that can support medical educators and trainees in discovering learning through trial and error in diverse clinical contexts. Accordingly, the present study was conducted to compare the effects of teaching gastrointestinal anatomy through graphic medicine and narrative visual storytelling versus traditional lecture-based instruction on medical students’ learning outcomes.</p> Methods <p>We conducted a mixed-methods study employing an explanatory sequential design. The sample comprised fifty second-year medical students at Shahid Beheshti University of Medical Sciences, who were randomly assigned (1:1) to either a comic-based intervention group (<i>n</i> = 25) or a traditional lecture control group (<i>n</i> = 25). Both groups participated in 8 weekly 60-minute sessions, designed to address identical learning objectives. The intervention group engaged with a professionally developed 37-page digital comic, accessible in print, via a mobile application, and through interactive web modules incorporating embedded quizzes and hotspots. The control group received conventional PowerPoint-based lectures delivered by an experienced anatomy faculty member, utilizing standard, engaging pedagogical practices and effective delivery techniques appropriate for didactic teaching. The primary outcome was knowledge acquisition, assessed using a validated 30-item multiple-choice test administered at baseline and immediately after the intervention. Secondary outcomes included measures of spatial ability, cognitive load (NASA-TLX), and student engagement surveys. Qualitative data were collected through weekly reflective journals (<i>n</i> = 50), think-aloud protocols (<i>n</i> = 16), and exit focus groups (four groups, 24 participants). Quantitative and qualitative findings were integrated using explanatory joint displays to provide a comprehensive understanding of the mechanisms underlying observed outcomes.</p> Results <p>Baseline knowledge scores were equivalent (comic: 26.60 ± 5.02; lecture: 25.88 ± 5.38; <i>p</i> = 0.61). At the immediate post-test, the comic group demonstrated significantly greater improvement (mean change: 32.12 ± 17.78 vs. 10.36 ± 2.60; t = 6.89, <i>p</i> &lt; 0.001, Cohen’s d = 1.21). The comic group reported lower cognitive load (<i>p</i> = 0.003) and higher engagement (<i>p</i> &lt; 0.001). Qualitative analysis revealed four themes: (1) Narrative Anchoring Enhanced Knowledge, (2) visual personification reduced abstraction, (3) interactive features promoted self-directed learning, and (4) peer discussion increased motivation. Qualitative findings explained that students’ reports of “seeing pathways in my mind” corresponded with higher spatial ability scores (<i>p</i> = 0.001).</p> Conclusions <p>Comic-based instruction significantly outperformed traditional lectures in knowledge acquisition and engagement. Sequential explanatory integration revealed that narrative visualization and reduced cognitive load serve as primary mechanisms. These findings support Dual Coding and Cognitive Load Theory and demonstrate the value of qualitative inquiry in understanding how visual narratives facilitate learning. Future research should explore longitudinal clinical application and implementation fidelity across diverse contexts.</p>