Herbicide resistance poses an escalating challenge to successful weed management in contemporary cropping systems, prompting growing interest in integrated strategies to reduce reliance on herbicides. Although cover cropping has long been recognized for its potential to suppress weeds, it has recently gained renewed attention as a weed management tool and for its ability to help producers achieve broader goals of soil health and environmental sustainability. Although research on its efficacy in the midsouthern United States has accumulated, a meta-analytic synthesis has been lacking. This meta-analysis synthesized 746 effect sizes from 27 peer-reviewed studies (selected based on explicit reporting of weed suppression metrics, conducted in the midsouthern United States between 1991 and 2023) to assess cover crop weed suppression in the midsouthern region, which includes Alabama, Arkansas, Louisiana, Mississippi, eastern Oklahoma, Tennessee, and eastern Texas. Six key moderators and their two-way interactions were evaluated: tillage status of no-cover-crop controls, cover crop termination timing, weed control evaluation timing, cover crop type, weed functional group, and crop type, using a multivariate framework capturing study-level variation. The overall effect size was 36 (confidence interval [CI], 25–47], with most moderator levels showing positive effect sizes. Suppression was pronounced against no-till controls (mean difference [MD] = 43; CI, 30–55), while tilled controls exhibited moderated effects (MD = 27; CI, 14–39) due to the inherent weed suppression provided by tillage. Effects were greater for early evaluation timing (MD = 47; CI, 33–61) than late timing (MD = 34; CI, 20–48). Grass-legume mixtures provided the greatest suppression (MD = 70; CI, 56–84), while brassicas were ineffective (MD = 13; CI, 0–27). However, substantial two-way interactions among these moderators were prevalent, accompanied by high heterogeneity, indicating complex context specificity. Nonetheless, these findings highlight the weed suppression potential of cover crops and provide agroecologically informed quantitative insights into using cover crops for weed management in the region.