This study is aimed to investigate the effectiveness of problem-based learning combined with simulation on students' problem-solving and creative thinking skills. By employing a quasi-experimental design, this study used essay and problem-based tests as the instruments to evaluate problem-solving and creative thinking skills of 192 students. These students were categorized into three groups: experimental group I (n = 68) receiving instruction using problem-based learning combined with simulation, experimental group II (n = 60) receiving instruction with problem-based learning only, and control group (n = 64) receiving instruction with a conventional method. Using a multivariate analysis of covariance, the results revealed that problem-solving and creative thinking skills taught by problem-based learning combined with simulation were significantly improved as compared to those in experimental group II and control group. In addition, a positive relationship was identified between students' problem-solving skills and their creative thinking skills. Ultimately, this study shows that instruction using problem-based learning combined with simulation method is much more effective than using either problem-based learning only or a conventional teaching method.