Benefits of metacognition and active learning on student performance are well understood; however, little is known about the effect of the "explicit teaching of metacognition" combined with active learning on student performance in chemistry courses. Using a quasi-experimental study design, we investigated: (1) differences in performance in the General Chemistry I course between students exposed to the explicit teaching of metacognition combined with active learning (treatment group) and their counterparts who were exposed to active learning alone (comparison group) and (2) the effect of the teaching method, gender, race/ethnicity, first-generation status, and preterm overall GPA on student performance, after controlling for ACT math scores, data consisting of exam scores on three midterm exams, and a cumulative final exam. Independent t-test results indicated that the treatment group performed significantly better than the comparison group on the midterm exam 3 and the cumulative final exam (p < 0.05), with mean differences of 6% and 5%, respectively. Descriptive statistics also indicated 8% and 10% lower numbers of DF letter grades (DFs) in the exam 3 and the final exam, respectively, and an 8% lower number of withdrawals from the course (Ws) for the treatment group compared to those of the comparison group. Hierarchical regression results indicated that being in the treatment group increased the performances in exam 3 and the final exam by 6.11 and 4.20 points, respectively. The increase was statistically significant (p < 0.001). Results suggest that metacognitive instruction infused with active learning has a significant effect on student performance in General Chemistry, particularly on cognitively demanding chemistry concepts.