Lithium is a highly effective medication for bipolar disorder, but its mechanism of action remains unknown. In this study, brain MRI scans and blood samples for gene expression (total of 110 scans and 109 blood samples) were collected from 21 bipolar subjects before and after 2 and 8 weeks of lithium monotherapy and at the same time-points from untreated 16 healthy controls. We used linear mixed-effects models to identify brain structural features and genes with expression changed after lithium treatment, with correction for multiple testing, and correlated their concurrent changes to identify molecular pathways associated with lithium effects. There are significant increases in gray matter fraction, global cortical thickness, and the frontal and parietal cortices after 8 weeks of lithium treatment (corrected p < 0.05). Volume increases were also seen for putamen, hippocampus, thalamic nuclei, and thalamic substructures. Several genes showed significant expression changes, and 14 gene pathways were identified for the present integration analysis. Of these, nine pathways had significant correlations with structural changes (FDR < 0.05). Three neurotrophy-related pathways (GDNF family of ligands, NFAT immune-response, and p53-signaling pathway) correlated with structural changes in multiple regions. Mediation analysis showed that the sphingomyelin metabolism pathway is associated with HAM-D change (p < 0.01), and this effect is mediated via the volume of mediodorsal thalamus (p < 0.03). In summary, the integration of lithium effects on brain structural and peripheral gene expression changes revealed effects on several neurotrophic molecular pathways, which provides further insights into the mechanism of lithium action.