Genomic advances have contributed to a proliferation of newborn screening (NBS) programs. Psychosocial consequences of NBS have been identified as risks to these public health initiatives. Following PRISMA guidelines, this systematic review synthesizes findings from 92 evidence-based, peer-reviewed research reports published from 2000 through 2020 regarding psychosocial issues associated with NBS. Results describe parents’ knowledge of and attitudes towards NBS, reactions to and understanding of positive NBS results, experiences of communication with health providers, decisions about carrier testing, and future pregnancies. Findings also explain the impact of positive NBS results on parent–child relationships, child development, informing children about carrier status, family burden, quality of life, and disparities. In conclusion, psychosocial consequences of receiving unexpected neonatal screening results and unsolicited genetic information remain significant risks to expansion of NBS. Findings suggest that risks may be mitigated by improved parent NBS education, effective communication, individualized genetic counseling, and anticipatory developmental guidance. Clinicians need to take extra measures to ensure equitable service delivery to marginalized subpopulations. Future investigations should be more inclusive of culturally and socioeconomically diverse families and conducted in low-resource countries. Providing these countries with adequate resources to develop NBS programs is an essential step towards achieving international health equity. View Full-Text ►▼ Show Figures This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.