BACKGROUND: Pre-exposure prophylaxis (PrEP) represents a proven biomedical strategy to prevent HIV transmissions among men who have sex with men (MSM) in the United States (US). Despite the design and implementation of various PrEP-focus interventions in the US, aggregated evidence for enhancing PrEP uptake and adherence is lacking. The objective of this systematic review is to synthesize and evaluate interventions aimed to improve PrEP uptake and adherence among MSM in the US, and identify gaps with opportunities to inform the design and implementation of future PrEP interventions for these priority populations. METHODS: We followed the PRISMA guidelines and conducted a systematic review of articles (published by November 28, 2021) with a focus on PrEP-related interventions by searching multiple databases (PubMed, MEDLINE, Web of Science and PsycINFO). Details of PrEP interventions were characterized based on their socioecological level(s), implementation modalities, and stage(s) of PrEP cascade continuum. RESULTS: Among the 1363 articles retrieved from multiple databases, 42 interventions identified from 47 publications met the inclusion criteria for this review. Most individual-level interventions were delivered via text messages and/or apps and incorporated personalized elements to tailor the intervention content on participants' demographic characteristics or HIV risk behaviors. Interpersonal-level interventions often employed peer mentors or social network strategies to enhance PrEP adoption among MSM of minority race. However, few interventions were implemented at the community-, healthcare/institution- or multiple levels. CONCLUSIONS: Interventions that incorporate multiple socioecological levels hold promise to facilitate PrEP adoption and adherence among MSM in the US given their acceptability, feasibility, efficacy and effectiveness. Future PrEP interventions that simultaneously address PrEP-related barriers/facilitators across multiple socioecological levels should be enhanced with a focus to tackle contextual and structural barriers (e.g., social determinants of health, stigma or medical mistrust) at the community- and healthcare/institution-level to effectively promote PrEP use for MSM of color.