Objective: This study assessed whether perceived social support (PSS) is a factor in improving physical and functional well-being observed among cancer patients receiving collaborative depression care. Methods: A secondary analysis was conducted of data collected in a randomized clinical trial testing the effectiveness of collaborative depression care. PSS was measured at 12 months; physical and functional well-being were assessed at 18 and 24 months post-baseline. Mediation analyses via a bootstrapping method were conducted. Results: Significant mediation of PSS at 12 months predicted better physical and functional well-being at 18 months and 24 months. Conclusion: Depressed cancer survivors are likely to benefit when social workers provide psychosocial depression care aimed at activating social support, thereby improving physical and functional well-being.