Background: While gamification is increasingly used in higher education, its impact on the specific dimensions of cognitive load particularly in complex subjects like histology remains underexplored. This study aimed to investigate the effect of gamification-based microlearning on students’ overall cognitive load in histology, with a specific interest in its potential differential impact on extraneous and germane cognitive load. Methods: This quasi-experimental study employed a pretest-posttest design with a control group. The sample consisted of 27 undergraduate biology students from Arak University, enrolled between January and June 2024, who were randomly allocated to either an experimental group (n = 14) or a control group (n = 13). Participants in the experimental group were taught histology using a specially developed gamified microlearning application over a 14-week period, whereas the control group received conventional lecture-based instruction. Cognitive load was assessed using the Paas Cognitive Load Scale, and the primary outcome was evaluated through a change score analysis. All statistical analyses were performed using IBM SPSS Statistics, version 23. Results: Analysis of change scores indicated a substantial difference between groups. The experimental group demonstrated a significant decrease in cognitive load (Mean = −7.71, SD = 2.76), while the control group experienced a modest increase over time (Mean = 2.31, SD = 5.11). An independent-samples t-test indicated that the difference in change scores between the two groups was statistically significant (p < 0.001). Furthermore, the effect size was exceptionally large (Cohen’s d = 2.47). Conclusion: Gamified microlearning appears to be an effective instructional approach for reducing cognitive load in complex scientific subjects. The results indicate that this integrated method may enhance the efficient use of cognitive resources. Future studies should include larger sample sizes, distinguish among different types of cognitive load, and investigate long-term outcomes as well as applicability across various disciplines.