This systematic review and meta-analysis aims to compare the effects of couple-based prevention interventions against individual-level interventions on HIV prevention in randomized controlled trials (RCTs), identify potential moderators, and assess study quality. Eleven RCTs were included, comprising 3933 couples in the intervention group and 7125 individuals in the individual control group, predominantly in heterosexual couples from the USA and Africa. Couple-based interventions had a more significant effect in promoting condom use and HIV testing. Education levels of high school or above, residence in low- and middle-income countries, and intervention design incorporating HIV counseling and testing were associated with higher odds of condom use. The quality assessment analysis identified methodological and theoretical heterogeneity factors. Evidence of couple-based HIV prevention RCTs among men who have sex with men, injecting drug users, sex workers, and transgender women warrant further investigation. Recommendations are made to improve the quality and replicability of future intervention studies.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10461-022-03768-5.