Immuno-metabolic dysregulation is implicated in mood disorders and elucidating non-invasive brain correlates may aid clinical translation of pathomechanism. This study aims to investigate the interrelationship between peripheral inflammation and body mass index (BMI) and their effects on white matter (WM) microstructure and free water (FW) in bipolar II depression (BDII-D). Voxel-wise FW and FW-corrected fractional anisotropy (FAt) were compared between 146 BDII-D and 151 healthy controls (HCs) using FSL Randomise. Partial correlations were used to explore associations between BMI, peripheral inflammation, FW measures, and psychiatric symptoms. Moderation analysis examined the interrelationships among BMI, peripheral inflammation, and FW measures. BDII-D showed lower FAt in the genu of the corpus callosum (CC) and bilateral anterior corona radiata, and higher FW in the body of the CC compared with HCs. Higher BMI was linked to lower global FAt (q < 0.001), while higher peripheral inflammation was associated with higher global FW (q ≤ 0.01) in BDII-D. Lower FAt in the genu of the CC and higher FW in the body of CC were significantly related to higher BMI, inflammation, and greater depressive symptoms (q < 0.05). Low-grade Inflammation moderated the relationship between higher BMI and lower FAt in the genu of the CC in BDII-D (B = −3.094e−05, p < 0.001). We found evidence for a mechanistic link between immune-metabolic dysregulation and altered connection in BDII-D. Next to mediating BMI effects on WM integrity, there seems to exist specific relationships between inflammation and BMI with different MR-based tract markers that need further investigation.