Purpose: This study aimed to investigate the potential effects of problem-based learning (PBL), predict observe explain (POE), and PBLPOE on students' problem-solving skills and self-efficacy in Biology. This research is based on various facts that problem-solving skills and self-efficacy of Indonesian students in biology subjects are still low. Research Methods: This quasi-experiment employed a pretest-posttest non-equivalent control group design. One hundred and thirty-two (132) tenth graders (aged 15 to 17) from Bengkulu, Indonesia, participated in this study. The participants were homogenous concerning academic abilities. Data were collected using an essay test and observation sheets. The essay test was developed to examine the students' problem-solving skills, and observation sheets were used to evaluate the students' self-efficacy. The data were analyzed using ANCOVA and Least Significant Different (LSD) test. Findings of the study suggest that PBLPOE has a more significant effect on students' problem-solving skills and self-efficacy compared to PBL, POE, and conventional learning. The highest scores of problem-solving skills and self-efficacy were obtained by students from the PBLPOE class, followed by the PBL, POE, and conventional groups. Implications for Research and Practice: Based on the results of this study, it is evident that PBLPOE is effective in fostering students' problem-solving skills and self-efficacy; thus, the use of PBLPOE in Biology classrooms is highly recommended.