This review identifies which elements of home-based comprehensive sexual health care (home-based CSH) impacted which key populations, under which circumstances. A realist review of studies focused on home-based CSH with at least self-sampling or self-testing HIV and additional sexual health care (e.g., treatment, counseling). Peer-reviewed quantitative and qualitative literature from PubMed, Embase, Cochrane Register of Controlled Trials, and PsycINFO published between February 2012 and February 2023 was examined. The PRISM framework was used to systematically assess the reach of key populations, effectiveness of the intervention, and effects on the adoption, implementation, and maintenance within routine sexual health care. Of 730 uniquely identified records, 93 were selected for extraction. Of these studies, 60% reported actual interventions and 40% described the acceptability and feasibility. Studies were mainly based in Europe or North America and were mostly targeted to MSM (59%; 55/93) (R). Overall, self-sampling or self-testing was highly acceptable across key populations. The effectiveness of most studies was (expected) increased HIV testing. Adoption of the home-based CSH was acceptable for care providers if linkage to care was available, even though a minority of studies reported adoption by care providers and implementation fidelity of the intervention. Most studies suggested maintenance of home-based CSH complementary to clinic-based care. Context and mechanisms were identified which may enhance implementation and maintenance of home-based CSH. When providing the individual with a choice of testing, clear instructions, and tailored dissemination successful uptake of STI and HIV testing may increase. For implementers perceived care and treatment benefits for clients may increase their willingness to implement home-based CSH. Therefore, home-based CSH may determine more accessible sexual health care and increased uptake of STI and HIV testing among key populations.