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This study aimed to explore the mediating effects of attitudes toward science on the relationship between inquiry-based practices and scientific literacy using data from eight countries in the 2015 Program for International Student Assessment. Multilevel structural equation modeling results indicated that the direct effect of inquiry-based practices on scientific literacy was negative, but it was positive on three dimensions of science attitudes, i.e., interest in science, self-efficacy, and instrumental motivation. The indirect effects of inquiry-based practices on scientific literacy via interest in science and self-efficacy were positive, yet it was negative via instrumental motivation. This study may suggest ways for educators to plan and implement effective inquiry-based pedagogical strategies aimed at improving student science attitudes and scientific literacy.