OBJECTIVE: To conduct a systematic review and meta-analyses to assess the effect of manual therapy interventions for healthy but unsettled, distressed and excessively crying infants and to provide information to help clinicians and parents inform decisions about care. METHODS: We reviewed published peer-reviewed primary research articles in the last 26 years from nine databases (Medline Ovid, Embase, Web of Science, Physiotherapy Evidence Database, Osteopathic Medicine Digital Repository , Cochrane (all databases), Index of Chiropractic Literature, Open Access Theses and Dissertations and Cumulative Index to Nursing and Allied Health Literature). Our inclusion criteria were: manual therapy (by regulated or registered professionals) of unsettled, distressed and excessively crying infants who were otherwise healthy and treated in a primary care setting. Outcomes of interest were: crying, feeding, sleep, parent-child relations, parent experience/satisfaction and parent-reported global change. RESULTS: Nineteen studies were selected for full review: seven randomised controlled trials, seven case series, three cohort studies, one service evaluation study and one qualitative study.We found moderate strength evidence for the effectiveness of manual therapy on: reduction in crying time (favourable: -1.27 hours per day (95% CI -2.19 to -0.36)), sleep (inconclusive), parent-child relations (inconclusive) and global improvement (no effect). The risk of reported adverse events was low: seven non-serious events per 1000 infants exposed to manual therapy (n=1308) and 110 per 1000 in those not exposed. CONCLUSIONS: Some small benefits were found, but whether these are meaningful to parents remains unclear as does the mechanisms of action. Manual therapy appears relatively safe. PROSPERO REGISTRATION NUMBER: CRD42016037353.