HIV pre-exposure prophylaxis (PrEP) is highly effective at preventing HIV; however, PrEP use among transgender individuals remains low. We conducted a systematic review to identify barriers and facilitators to PrEP uptake, adherence, and persistence among transgender individuals in the United States. We conducted a literature search in PubMed and CINAHL databases in March 2021 and followed PRISMA guidelines. Studies were eligible if they were published in a peer-reviewed journal and reported interest, uptake, adherence, and/or persistence of PrEP use among transgender individuals. Articles that did not disaggregate results for transgender participants were excluded. Data from included articles were coded using content analysis and narratively synthesized using a framework matrix. We screened 254 unique articles published after US Food and Drug Administration approval of PrEP, and 33 articles were included in the review. Five themes were identified in the literature, including (1) PrEP concentrations were lower among individuals taking feminizing hormones, but the difference did not appear clinically significant; (2) concerns regarding interactions between gender-affirming hormone therapy and PrEP remain a large barrier; (3) PrEP initiation may facilitate increased self-advocacy and self-acceptance; (4) lack of trust in medical institutions impacts PrEP uptake; and (5) social networks have a significant influence on PrEP knowledge, interest, and adherence. Additional research is needed involving transgender men and nonbinary persons, and efforts to improve PrEP persistence among the transgender community are needed. Training health care providers to provide inclusive and affirming care is perhaps one of the strongest areas for intervention to increase PrEP uptake and persistence.