Background: Luteal phase support (LPS) with progesterone is essential for successful implantation and early pregnancy maintenance in IVF cycles. Although various administration routes exist (oral, vaginal, intramuscular, subcutaneous), the comparative effectiveness of combined (dual or triple) versus single-route progesterone regimens remains uncertain due to limited high-quality randomized controlled trials. Methods: A systematic review was conducted to evaluate studies comparing pregnancy outcomes in IVF cycles using combined versus single-route progesterone administration for LPS. A comprehensive literature search was performed to identify retrospective, prospective, and randomized controlled studies published in peer-reviewed journals. Data regarding clinical pregnancy, live birth, miscarriage, and implantation rates were collected and synthesized narratively due to heterogeneity among included studies. Results: Most studies did not demonstrate statistically significant differences in outcomes between single-route and combined progesterone regimens, particularly when dydrogesterone was included. However, certain combinations, especially those involving oral dydrogesterone alongside vaginal or intramuscular progesterone, were associated with improved live birth and clinical pregnancy rates. Despite these encouraging findings, the lack of adequately powered RCTs and the methodological variability among studies limit the generalizability of the results. Conclusion: While single-route progesterone administration remains effective for luteal phase support in IVF cycles, emerging evidence suggests that individualized combined regimens may enhance pregnancy outcomes. The physiological rationale for combined administration, offering both systemic and local endometrial support, is compelling. Further well-designed randomized controlled trials with standardized protocols are necessary to establish evidence-based guidelines for optimal LPS.