We conducted a comprehensive, systematic review and meta-analysis on the effects of the BSCS 5E Instructional Model--and its related variants--on science, math, and motivation outcomes. The 5E Instructional Model is a framework for delivering STEM instruction that is based on constructivist learning theory; it has been used throughout the U.S. and other countries, particularly in Turkey. Despite its wide usage, no comprehensive systematic review and meta-analysis on the effects of 5E and related models has yet been conducted. Our search and screening procedures yielded 61 randomized controlled trial studies, estimating 156 effect sizes; 70% of studies met WWC standards with or without reservations. We found that the 5E instructional model resulted in improved science outcomes (g = 0.82, 95% CI [0.67, 0.97]), but a large amount of heterogeneity requires some caution (t = 0.56). We explored numerous explanations for the effect heterogeneity and provided practical recommendations.