Background Colic is defined as periods of inconsolable crying, fussing, or irritability that have no apparent cause and present in healthy infants under 5 months of age. Although colic is a benign and self-limiting condition, it can be distressing to parents and there are few robust treatment interventions. This systematic review explored the evidence for administration of probiotics to prevent or decrease symptoms of colic. Methods Literature searches were conducted in PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane Library, and Web of Science. Sample Twenty articles were included: 15 randomized controlled trials and 5 meta-analyses. Results Based on the evidence in this systematic review, the oral administration of probiotics to breastfed infants with colic resulted in at least a 50% reduction in crying time compared with placebo. Efficacy of probiotics to reduce colic symptoms in formula-fed infants needs further study. In this review, we did not find evidence to support or refute efficacy of probiotics to prevent infantile colic. Clinical Implication: Probiotics (especially the strain Lactobacillus reuteri DSM 17938) can safely be recommended if parents desire a treatment option for their infants with colic.