Intracerebral hemorrhage (ICH) is a serious cerebrovascular disease with high morbidity, mortality, and disability rates, largely due to neuroinflammation. Diosmetin, a natural flavonoid, has known neuroprotective effects in cerebral ischemia/reperfusion models but has been less studied in ICH. Our previous study developed diosmetin-loaded lactoferrin-modified long-circulating liposomes (Lf-Dios-Lcl), which penetrate the BBB and improve diosmetin bioavailability and brain distribution. In this study, we found that diosmetin reduced the levels of proinflammatory cytokines (IL-1β and TNF-α) and increased the level of the anti-inflammatory cytokine IL-10 in LPS-induced BV2 cells, promoting microglial polarization toward the anti-inflammatory M2 phenotype. In ICH model rats, Lf-Dios-Lcl (1 mg/kg) effectively reduced neuroinflammation, decreased IL-1β and TNF-α levels, increased IL-10 levels, and increased the proportion of CD206-positive microglia in brain tissues. Moreover, Lf-Dios-Lcl significantly downregulated p-p38 expression, suggesting that p38 signaling activation was inhibited. Overall, Lf-Dios-Lcl demonstrated brain-targeting properties and antineuroinflammatory effects by modulating microglial polarization via the p38 pathway.