This article summarizes the results from systematic reviews of human immunodeficiency virus (HIV) prevention interventions for people who use drugs (PWUD). We performed an overview of reviews, meta-analysis, meta-epidemiology, and PROSPERO Registration CRD42017070117. We conducted a comprehensive systematic literature search using the Centers for Disease Control and Prevention HIV/AIDS Prevention Research Synthesis Project database to identify quantitative systematic reviews of HIV public heath interventions with PWUD published during 2002-2017. We recombined results of US studies across reviews to quantify effects on HIV infections, continuum of HIV care, sexual risk, and 5 drug-related outcomes (sharing injection equipment, injection frequency, opioid use, general drug use, and participation in drug treatment). We conducted summary meta-analyses separately for reviews of randomized controlled trials (RCTs) and quasi-experiments. We stratified effects by 5 intervention types: behavioral-psychosocial (BPS), syringe service programs (SSP), opioid agonist therapy (OAT), financial and scheduling incentives (FSI), and case management (CM). We identified 16 eligible reviews including >140 US studies with >55 000 participants. Summary effects among US studies were significant and favorable for 4 of 5 outcomes measured under RCT (eg, reduced opioid use; odds ratio [OR] = 0.70, confidence interval [CI] = 0.56-0.89) and all 6 outcomes under quasi-experiments (eg, reduced HIV infection [OR = 0.42, CI = 0.27-0.63]; favorable continuum of HIV care [OR = 0.68, CI = 0.53-0.88]). Each intervention type showed effectiveness on 1-6 outcomes. Heterogeneity was moderate to none for RCT but moderate to high for quasi-experiments. Behavioral-psychosocial, SSP, OAT, FSI, and CM interventions are effective in reducing risk of HIV and sequelae of injection and other drug use, and they have a continuing role in addressing the opioid crisis and Ending the HIV Epidemic.