Bridging theoretical learning with practical applications is crucial in biology education, where the relevance of concepts directly influences learners' adaptability across educational contexts. This study assessed how Design-Based Biology Instruction (DBBI) impacts students' cognitive flexibility. Employing a three-group pretest-posttest quasi-experimental design, 141 senior high school students participated in DBBI, Problem-Based Learning (PBL), and Conventional Teaching interventions. Results highlighted DBBI's effectiveness in enhancing students' cognitive flexibility, emphasizing its role in bridging the theory-practice gap in biology education. Moving forward, further studies are necessary to address identified limitations. Methodological refinements, larger sample sizes, and exploration of diverse educational settings could provide deeper insights into the implementation and effects of DBBI on student outcomes. These parallel investigations are critical for enriching existing literature and advancing discussions on innovative instructional approaches in biology education. By addressing these areas, future research can significantly enhance educational practices that promote cognitive flexibility and practical understanding among biology learners.