Modern pedagogy underlines the voice of learners, the questions they raise, their ability to synthesize and analyze knowledge, and their participation in scientific inquiry within a cooperative system, rather than focusing on students‘ ability memorize information. Therefore, this study examined the effect of the Science Process Skills-Based Teaching Method (SPSBTM) on students‘ learning outcomes- specifically academic achievement, epistemological beliefs, and classroom engagement- among 78 secondary school students in Woldia, Ethiopia. This study employed a quantitative-led mixed-methods research approach. The quantitative component used a pretest-posttest non-equivalent comparison group quasi-experimental design, while the qualitative component employed thematic analysis. A multistage sampling technique was used to select two intact classes from two public secondary schools, and the classes were randomly assigned as an experimental group (EG) and comparison group (CG). Data were collected using several instruments: a Cell Biology Academic Achievement Test (CBAT) to measure academic achievement, an Epistemological Beliefs Questionnaire (EBQ) and semi-structured interview to assess students‘ epistemological beliefs, and a Biology Lesson Engagement Questionnaire (BLEQ) to evaluate classroom engagement. Quantitative data were analyzed using independent samples t-test and ANCOVA, while thematic analysis was used for qualitative data. The independent samples t-test revealed no significant differences in academic achievement, epistemological beliefs, or classroom engagement between the two groups or between genders in the EG prior to the intervention. After the intervention, ANCOVA results showed significant differences in academic achievement (EG, M= 23.26; CG, M=18.65; η²=0.366, p<0.001) and overall epistemological beliefs (EG, M=4.33; CG, M=4.09; η²=0.415, p<0.001) between groups. Thematically coded combined overall qualitative results also indicated that EG students (83.3%) had expert-like beliefs than the CG students (70.8%). The independent samples t-test also revealed statistically significant differences in overall engagement scale mean scores between the groups (EG, M = 4.22; CG, M = 3.87; t (76) = 6.805, p = <0.001; Cohen‘s d = 1.154). Additionally, there was a statistically significant mean difference between genders in the EG students' engagement (males, M=4.29; females, M=4.14; t (36) = 2.367, p = 0.023, d = 0.768) in favor of males, specifically in emotional and behavioral engagement. However, there were no significant differences in academic achievement or epistemological beliefs between genders in the EG. The study concludes that SPSBTM was more effective in improving students‘ learning outcomes compared to conventional teaching methods. Therefore, it is recommended that biology curriculum experts and teachers consider integrating and implementing the SPSBTM in biology education to enhance student‘s learning outcomes. Keywords: Academic achievement, cell biology, engagement, epistemological beliefs, science process skills, secondary school