ObjectiveThis study aims to comprehensively analyze and evaluate the efficacy and safety of daridorexant in treating insomnia.MethodsThis study conducted a systematic search across 7 electronic databases: PubMed, Web of Science, Cochrane Library, Embase, ClinicalTrials.gov, Scopus and the World Health Organization International Clinical Trials Registry Platform [http://www.who.int/ictrp/search/en/]). The review was registered (CRD420251174557). The effectiveness indicators included objective measures such as latency to persistent sleep (LPS) and wake time after sleep onset (WASO), as well as subjective measures including subjective latency to sleep onset (sLSO), subjective total sleep time (sTST), Visual analog scale (VAS), the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) sleepiness domain score, and insomnia severity index (ISI). The safety indicators encompassed treatment-emergent adverse events (TEAEs), adverse events leading to premature termination, severe adverse events (SAEs), and adverse events of special interest (AESIs).ResultsThis study included a total of 5 articles, 6 RCTs, with a total of 2905 patients with insomnia. In terms of objective indicators, during the initial treatment stage (1–2 days), daridorexant was superior to the placebo; this advantage persisted at 1 month; and at 3 months, the 25 mg dose remained effective. In terms of subjective indicators, at 1 month, Daridorexant outperformed the placebo in most of the indicators; at 3 months, the 25 mg dose remained effective in sTST (SMD 0.25 [0.14, 0.36], P < 0.0001, I2 = 52%). In safety indicators, TEAEs, SAEs and adverse events leading to premature termination at each dose level were comparable to those of the placebo group. However, the combined effect indicated that the overall risk of TEAEs in daridorexant was higher (RR 1.15 [1.05, 1.25], P = 0.003, I2 = 0%). 25mg daridorexant significantly increased the risk of AESIs compared to placebo, while 10mg and 50 mg did not reach statistical significance, but overall still suggested an elevated risk (RR 4.00 [1.64, 9.76], P = 0.002, I2 = 0%).ConclusionThe efficacy of daridorexant in the treatment of insomnia is dose-dependent, with doses of 25 mg and 50 mg demonstrating significant improvements in both subjective and objective sleep metrics in the short term (1 month). Notably, the efficacy of the 25 mg dose is sustained in objective metrics over the medium term (3 months). Daridorexant overall performance is relatively safe, but the 25 mg dose may be associated with an increased risk of AESIs.Systematic Review RegistrationIdentifier, CRD420251174557.