The study investigated the effect of problem-based learning strategy in fostering creative thinking skills among senior secondary chemistry students in Ogoja Education Zone of Cross River State, Nigeria. Three research questions and three null hypotheses guided the study. A pre-test, post-test non-randomized control group quasi experimental design was adopted while a sample of one hundred and twenty-five (125) senior secondary two (SS 2) Chemistry students drawn from a population of 2533 chemistry students participation in the study. One co-educational school each was selected from two out of five Local Government Areas in the zone through purposive and simple random sampling techniques. An intact class from each of the two schools was randomly assigned to experimental and controls groups. An instrument titled Creative Thinking Skills Acquisition Scale (CTSAC) with a reliability index of 0.09 was used for data collection. The data obtained was analyzed using mean scores to answer the research questions and the analysis of covariance (ANCOVA) used to test the hypotheses at 0.05 level of significant. The results showed that students exposed to problem-based learning strategy exhibited a higher propensity in the acquisition of creative thinking skills than those taught using the conventional lecture method of instruction. The result further indicated that there is no significant influence of gender on students’ acquisition of creative thinking skills. Based on the result obtained, it was therefore recommended that problem-based learning strategy be used to teach chemistry and other STEM subjects in secondary school to help students develop creative thinking skills.