OBJECTIVES: The aim of this study was to conduct a systematic review, meta-analysis, and metaregression to determine the current best available evidence of the efficacy and safety of foot reflexology for adult depression, anxiety, and sleep quality. METHODS: Electronic databases (PubMed, ClinicalKey, ScienceDirect, EMBASE, PsycINFO, and the Cochrane Library) were searched till August, 10, 2020, and the validity of the eligible studies was critically appraised. Randomized controlled trials comparing foot reflexology groups with control groups for adult depression, anxiety, and sleep quality were included. Twenty-six eligible studies were included to assess the effect of foot reflexology intervention on the reducing symptoms of depression and anxiety and improving quality of sleep, respectively, as the primary outcome. RESULTS: Twenty-six randomized controlled trials involving 2,366 participants met the inclusion criteria. The meta-analyses showed that foot reflexology intervention significantly improved adult depression (Hedges'  = -0.921; 95% CI: -1.246 to -0.595;  < 0.001), anxiety (Hedges'  = -1.237; 95% CI -1.682 to -0.791;  < 0.001), and sleep quality (Hedges'  = -1.665; 95% CI -2.361 to -0.970;  < 0.001). Metaregression reveals that an increase in total foot reflexology time ( = 0.002) and duration ( = 0.01) can significantly improve sleep quality. CONCLUSIONS: Foot reflexology may provide additional nonpharmacotherapy intervention for adults suffering from depression, anxiety, or sleep disturbance. However, high quality and rigorous design RCTs in specific population, along with an increase in participants, and a long-term follow-up are recommended in the future.