Abstract Background It is not well established how psychosocial factors like social support and depression affect health-related quality of life in multimorbid and elderly patients. We investigated whether depressive mood mediates the influence of social support on health-related quality of life. Methods Cross-sectional data of 3,189 multimorbid patients from the baseline assessment of the German MultiCare cohort study were used. Mediation was tested using the approach described by Baron and Kenny based on multiple linear regression, and controlling for socioeconomic variables and burden of multimorbidity. Results Mediation analyses confirmed that depressive mood mediates the influence of social support on health-related quality of life (Sobel’s p < 0.001). Multiple linear regression showed that the influence of depressive mood (β = −0.341, p < 0.01) on health-related quality of life is greater than the influence of multimorbidity (β = −0.234, p < 0.01). Conclusion Social support influences health-related quality of life, but this association is strongly mediated by depressive mood. Depression should be taken into consideration in research on multimorbidity, and clinicians should be aware of its importance when caring for multimorbid patients. Trial registration ISRCTN89818205