Introduction We introduce moderated network analysis as an integrative approach to assess the moderation effects of race on the relationship between C-reactive protein (CRP) and depression symptoms in older adults. This study further explores how the observed relationships differ adjusting for social relationships. Methods This secondary analysis of cross-sectional data from the National Social Life, Health, and Aging Project (2010–2011) includes 2,880 older adults. We used different depression symptom domains (depressed affect, low positive affect, somatic symptoms, and interpersonal problems) from the Center for Epidemiologic Studies-Depression Scale. Social relationships were assessed with measures of social integration, social support, and social strain. The moderated networks were constructed using the R-package mgm. The racial moderator was coded as White/African American racial groups. Results In the moderated networks of CRP and depression symptoms, CRP–“interpersonal problems” edge was present only among African Americans. CRP–“somatic symptoms” edge was present in both racial groups with equal edge weights. After adjusting for social relationships, the aforementioned patterns remained the same, but the edge weights were attenuated. We additionally observed CRP–social strain and social integration–“depressed affect” edges only in African Americans. Discussion Race may moderate the relationship between the CRP and depression symptoms in older adults and social relationships might be important covariates to consider while analyzing them. This study as an initiation point; future network investigations would benefit from leveraging more contemporary cohorts of older adults, gaining a large sample size with diverse racial/ethnic backgrounds, and important covariates. Several important methodological issues of the current study are addressed.