Depression severely affects older adults in the United States. As part of the social environment, significant social support was suggested to ameliorate depression among older adults. We investigate how varying forms of social support moderate depressive symptomatology among older adults with multiple chronic conditions (MCC). Data were analyzed using a sample of 11,400 adults, aged 65 years or older, from the 2006–2012 Health and Retirement Study. The current study investigated the moderating effects of positive or negative social support from spouse, children, other family, and friends on the association between MCC and depression. A linear mixed model with repeated measures was used to estimate the effect of MCC on depression and its interactions with positive and negative social support in explaining depression among older adults. Varying forms of social support played different moderating roles in depressive symptomatology among older adults with MCC. Positive spousal support significantly weakened the deleterious effect of MCC on depression. Conversely, all negative social support from spouse, children, other family, and friends significantly strengthened the deleterious effect of MCC on depression. Minimizing negative social support and maximizing positive spousal support can reduce depression caused by MCC and lead to successful aging among older adults.