Critical thinking and problem-solving are essential 21st-century skills; however, they remain underdeveloped in Ethiopian secondary education, where biology instruction is often dominated by rote learning, low academic achievement, and limited integration of indigenous knowledge. These constraints reduce students‘ ability to apply biological concepts to real-life contexts. This study examined the effectiveness of problem-based scenarios (PBS) integrated with Ethiopian indigenous knowledge in enhancing Grade 10 students‘ academic achievement, critical thinking, and problem-solving skills in human biology. Using a design-based research approach with mixed methods, the study was conducted over eight weeks in three biology classes. One classs received problem based scenarios with incorporating indigenous knowledge, while the other received problem based scenario alone, the control class received conventional instruction. Data were collected through pre- and posttests, interviews, student reflections, and classroom observations, and analyzed using SPSS and iterative qualitative coding. Results showed that Intervention 2 produced the largest and most consistent statistically significant gains (p ≤ .043) in academic achievement, critical thinking, and problem-solving skills compared with Intervention 1 and the control group. Students demonstrated improved ability to generate practical, culturally relevant solutions to complex health-related scenarios. Gender had no significant main effect, although small interaction effects between gender and intervention were observed. The findings indicate that integrating problem-based scenarios with indigenous knowledge effectively enhances critical thinking, problem solving skills, and academic achievement in biology. To maximize impact, policymakers should institutionalize indigenous knowledge–integrated, problem-based biology instruction through curriculum reform, equitable digital access, and sustained teacher professional development. Educators should address technical constraints. Further research is recommended to refine instructional tools and improve inclusivity and learner engagement.