Cultural entities and local or national wisdom can serve to provide scientific knowledge to students, and the in-depth knowledge in the fields of science must be underpinned by critical thinking (CT). In a developing perspective, inquiry is the best way to train CT skills, and creativity becomes one of the supporting aspects. This study aimed to implement inquiry-creative learning integrated with ethnoscience to develop the CT skills of prospective science teachers (PSTs). The study applied the randomized pretest-posttest control design, involving two intervention groups, one with inquiry-creative learning integrated with ethnoscience (n = 29) and the other with traditional teaching (n = 26). The participants were PSTs at two universities in Indonesia. Each group was observed for their CT skills in line with CT indicators (CTi) and individual performance (CTs) using the pretest-posttest method and compared, and a valid essay test was applied to collect data. The CT skills data analysis was descriptive based on the average pretest-posttest and n-gain parameters. The effects of the two interventions on CT skills were analyzed using the t test (p < .05). After descriptive and statistical tests were carried out, the assessment of CT performance on participants in the two intervention groups showed different results. For the CTi and CTs, inquiry-creative learning integrated with ethnoscience had a better impact on training participants’ CT skills when compared to traditional instruction. The statistical analysis results showed a significant difference in the performance of CT skills in participants between the two groups being compared. The findings of this study emphasize that in relation to improving CT performance, teaching practice with inquiry-creative learning integrated with ethnoscience is most effective in improving the CT skills of PSTs. The advantages of the learning intervention are discussed and may contribute to the literature of future studies.