Mechanisms linking a proinflammatory diet to obesity remain under investigation. The ability of diet to influence the gut microbiome (GM) in creating chronic low-grade systemic inflammation provides a plausible connection to adiposity. Assess whether any associations seen between the Energy-Adjusted Dietary Inflammatory Index (E-DII score), total fat mass, visceral adipose tissue (VAT), or liver fat (percentage volume) operated through the GM or microbial related inflammatory factors, in a multiethnic cross-sectional study. In the Multiethnic Cohort–Adiposity Phenotype Study (812 men, 843 women, aged 60–77 y) we tested whether associations between the E-DII and total adiposity, VAT, and liver fat function through the GM, LPS, and high-sensitivity C-reactive protein (hs-CRP). DXA-derived total fat mass, MRI-measured VAT, and MRI-based liver fat were measured. Participants provided stool and fasting blood samples and completed an FFQ. Stool bacterial DNA was amplified and the 16S rRNA gene was sequenced at the V1–V3 region. E-DII score was computed from FFQ data, with a higher E-DII representing a more proinflammatory diet. The associations between E-DII score, GM (10 phyla, 28 genera, α diversity), and adiposity phenotypes were examined using linear regression and mediation analyses, adjusting for confounders. There were positive total effects (c) between E-DII and total fat mass (c = 0.68; 95% CI: 0.47, 0.90), VAT (c = 4.61; 95% CI: 2.95, 6.27), and liver fat (c = 0.40; 95% CI: 0.27, 0.53). The association between E-DII score and total fat mass was mediated by LPS, Flavonifractor, Ruminococcus gnavus group, and Tyzzerella. The association between E-DII score and ectopic fat occurred indirectly through Fusobacteria, Christensenellaceae R-7 group, Coprococcus 2, Escherichia-Shigella, Eubacterium xylanophilum group, Flavonifractor, Lachnoclostridium, Ruminococcus gnavus group, Tyzzerella, Ruminococcus gnavus group (VAT only), and α diversity (liver fat only). There was no significant association between E-DII score and adiposity phenotype through hs-CRP. Associations found between E-DII and adiposity phenotypes occurred through the GM and LPS.