Objective To classify NICU interventions for parental distress and quantify their effectiveness. Study design We systematically reviewed controlled studies published before 2017 measuring NICU parental distress, defined broad intervention categories, and used random-effects meta-analysis to quantify treatment effectiveness. Results Among 1643 unique records, 58 eligible trials predominantly studied mothers of preterm infants. Interventions tested in 22 randomized trials decreased parental distress (p < 0.001) and demonstrated improvement beyond 6 months (p < 0.005). In subgroup analyses, complementary/alternative medicine and family-centered instruction interventions each decreased distress symptoms (p < 0.01), with fathers and mothers improving to similar extents. Most psychotherapy studies decreased distress individually but did not qualify for meta-analysis as a group. Conclusion NICU interventions modestly reduced parental distress. We identified family-centered instruction as a target for implementation and complementary/alternative medicine as a target for further study. Investigators must develop psychosocial interventions that serve NICU parents at large, including fathers and parents of full-term infants.