This study examined how 465 socioeconomically disadvantaged middle school students used a multimedia-enriched problem-based learning (PBL) program. Using a mixed-methods design, we investigated the impact of PBL on students' performance, and relationship among students' self-efficacy, attitude toward science, and performance. The findings showed students' science knowledge increased significantly after using the PBL program and students practiced problem-solving, collaboration, and self-directed learning skills. While both genders increased their science knowledge significantly, the girls had a larger knowledge gain and more girls stated they learned problem-solving skills. Students' self-efficacy was a significant predictor of their science knowledge, and self-efficacy was a mediator between students' attitude and science knowledge. The findings contributed to much needed literature on PBL use for socioeconomically disadvantaged population.