This systematic review investigated the direct relationship between adverse childhood experiences (ACEs) and antidepressant medications (ADM). To expand a recent review (Nanni et al., 2012) and reflect the current understanding of the relationship between ACEs and ADM, we searched PsychInfo and Medline databases and cited references from 2010-2020. Terms searched included ADM and each of the ACEs as well as child abuse and maltreatment. Combined searches yielded 2219 articles (1780 after duplicate removal) for review with 20 articles meeting study criteria. Inclusion criteria included conjointly examining ACEs and ADM for depression in humans and exclusion criteria included bipolar and psychosis comorbidities. Most studies testing ADM efficacy or psychotherapy against or in conjunction with ADMs used clinical trials (often randomized) with some case series and cross-sectional studies. Findings showed ACES were associated with an increased likelihood of using ADMs, had an interaction between DNA methylation and ADM efficacy, are linked to suicide risk when using ADM, are linked to ADM responsiveness but response may be dependent on patient age or age when ACE(s) occurred, and no studies were found to support psychotherapy was superior to ADM alone or in combination. ADMs, endorsed in two or more studies, demonstrating success to reduce depressive symptoms with those with ACEs include vortioxetine, venlafaxine, fluoxetine, paroxetine, and citalopram/escitalopram. Reduced ADM responsiveness with those with ACEs could be related to an interaction with specific single nucleotide polymorphisms affecting serotonin and norepinephrine expression or timing of abuse (e.g., aged 4-7).