Physiology concepts, such as acid-base balance, may be difficult for students to understand. Systems modeling, a cognitive tool, allows students to visualize their mental model of the problem space to enhance learning and retention. We performed a within-subjects three-period randomized control comparison of systems modeling versus written discussion activities in an undergraduate asynchronous online Anatomy and Physiology II course. Participants (n = 108) were randomized to groups with differing treatment orders across three course units: endocrine, immune, and acid-base balance. Participants demonstrated content understanding through either constructing systems modeling diagrams (M) or written discussion posts (W) in a MWM, MMW, or WMM sequence. For each of three units, student performance was assessed on 6 standardized multiple-choice questions embedded within a 45-question exam. The same 6 questions per unit, 18 questions in total, were again assessed on the 75-question final exam. The groups demonstrated no significant difference in performance in the endocrine unit exam [mean difference (MD) = -0.036]. However, the modeling group outperformed the writing group in the immune unit exam (MD = 0.209) and widened the gap in the acid-base balance unit exam (MD = 0.243). On the final exam, performance was again higher for the modeling group on acid-base balance content, as mean difference increased to 0.306 despite the final exam content for acid-base balance being significantly more difficult compared to other units [modeling: F(2) = 29.882, P < 0.001; writing: F(2) = 25.450, P < 0.001]. These results provide initial evidence that participation in systems modeling activities may enhance student learning of difficult physiology content as evidenced by improved multiple-choice question performance.