Purpose: Acceptance of the International Classification of Functioning, Disability and Health (ICF) in research and clinical practice has been delayed, despite its multiperspective approach to health measurement. This review utilized the ICF to examine evidence on the associations between depressive symptoms and psychosocial functioning in a patient cohort: multiple sclerosis (MS). Research Method: Forty-nine studies, involving 7,548 adults with relapsing or progressive forms of MS, were quantitatively evaluated. Data were categorized according to ICF domains: activities of individuals along with their participation in life areas and influential environmental and personal factors. Effect size estimates, in the form of Pearson’s r, 95% confidence intervals and Fail-safe Ns were calculated. Results: Depression severity was linked to reduced social activities and participation levels (29%, n = 14 studies). Limited quality and/or frequency of informal support from family and friends was also identified as an environmental barrier to participation (29%, n = 14 studies). Intrapersonal markers of depressive symptomatology (e.g., low self-efficacy, anxiety, poor coping, illness attitudes and beliefs) were routinely reported (53%, n = 29 studies). Conclusions: The ICF can help guide the selection of clinical measures to assess psychosocial functioning in adults with MS and highlight areas necessitating further research and/or intervention. For those reporting depressed mood, this might include interventions premised on supporting activity and participation in addition to reinforcing interpersonal strengths. To enhance the utility of the ICF in MS care, further research is needed to operationalize its domains and to map this framework onto existing measurement tools.