The increasing need for innovative constructivist learning approaches in college STEM subject domains has necessitated the use of flipped instruction which infuses computer-assisted learning with face-to-face learning to achieve optimal learning. This meta-analysis investigates the effect of flipped instruction and the conditions under which it is beneficial or deleterious for college students learning in STEM subject domains. Overall, the meta-analysis results show that flipped instruction is an effective learning strategy for STEM subject domains. Moderator analyses reveal that pre-class instructional features, the structure of in-class activities, STEM subject domains, and test format moderated the overall effect size. Our findings indicate that flipped instruction yields robust learning benefits when the pre-class videos are accompanied by pre-class tasks for students to work on and collaborative in-class activities that allow them to interact with one another. These findings have implications for designing flipped instruction, particularly for STEM subject domains.