Critical thinking (CRT) skills transversally pervade education and nature of science (NOS) knowledge is a key component of science literacy. Some science education researchers advocate that CRT skills and NOS knowledge have a mutual impact and relationship. However, few research studies have undertaken the empirical confirmation of this relationship and most fail to match the two terms of the relationship adequately. This paper aims to test the relationship by applying correlation, regression and ANOVA procedures to the students’ answers to two tests that measure thinking skills and science definitions. The results partly confirm the hypothesised relationship, which displays some complex features: on the one hand, the relationship is positive and significant for the NOS variables that express adequate ideas about science. However, it is non-significant when the NOS variables depict misinformed ideas about science. Furthermore, the comparison of the two student cohorts reveals that two years of science instruction do not seem to contribute to advancing students’ NOS conceptions. Finally, some interpretations and consequences of these results for scientific literacy, teaching NOS (paying attention both to informed and misinformed ideas), for connecting NOS with general epistemic knowledge, and assessing CRT skills are discussed.