The majority of antidepressant medication trials have focused on adult populations (ages 18-65), with much less research in older and younger populations. Moreover, key differences in the efficacy and safety of antidepressants have been identified between these age groups. Ketamine has emerged as a promising new treatment for treatment resistant depression (TRD). The objective of this review is to summarize and synthesize the extant literature on the effectiveness, safety and tolerability of ketamine for depression in special age populations (age ≤18 and ≥ 60). Following PRISMA guidelines, a systematic review was performed, searching EMBASE, PsycInfo, and PubMed from inception through July 2020. Studies reporting the use of any ketamine formulation with variable routes of administration to treat clinically diagnosed depression in adolescents or older adults were included. Thirteen studies were included in the analysis and ten observed rapid (≤2 week latency) antidepressant effects following ketamine treatments, with better outcomes following larger, repeated doses, and in open-label rather than blinded settings. Two case reports in adolescents assessed measures of suicidal ideation and both found ketamine to effectuate rapid anti-suicidal effects. Ketamine appears to be safe and well-tolerated in adolescents and older adults. The small quantity, high heterogeneity, and generally low quality of available studies precludes statistical syntheses and significantly limits the strength of our conclusions. Preliminary proof-of-concept studies are promising, however, rigorously designed randomized controlled trials (RCTs) are still required to ascertain effectiveness, safety and tolerability in these groups.