Background: Intracerebral hemorrhage (ICH) is a common neurological emergency with higher mortality and disability rate than cerebral ischemia. Although diverse therapeutic interventions have been explored for potential neuroprotection from ICH, no effective drugs until now are available for improvement of survival rate or the life quality of survivors after ICH. Just like cerebral ischemia, inflammatory mechanism is highly thought to play a vital role in hemorrhagic brain injury. Ligustilide (LIG) has potent anti-inflammatory effects, which were shown to be closely related to its neuroprotective effects against ischemic brain injury. Senkyunolide H (SH) and senkyunolide I (SI) are natural degradation products of LIG, which contain the mother nucleus structure of LIG as that of phthalide. However, no reports have been retrieved about the neuroprotective effects of the three phthalide compounds on ICH, especially from the perspectives of inflammatory pathways. Accordingly, this study investigated the neuroprotective potentials and mechanisms of LIG, SH and SI on experimental ICH in mice. Methods: ICH was induced in adult male CD-1 mice by intracerebral injection of autologous blood. LIG, SH and SI, respectively, was administrated after ICH induction. Neurological deficits, brain edema, injury volume, the number of surviving/dying neurons and inflammatory gene expression were evaluated at 3 days after ICH. Results: Neurological deficits, brain edema, neuronal injury, microglia and astrocytes activation as well as peripheral immune cells infiltration were all significantly improved by LIG and SH, yet SI not. Moreover, the expression of TLR4, p-NF-kappa B p65, TNF-alpha and IL-6, was significantly downregulated by LIG and SH treatment. So was Prx1 expression and release. Conclusions: LIG and SH provide the potent neuroprotective effects against hemorrhagic stroke by inhibiting Prx1/TLR4/NF-kappa B signaling and the subsequent immune and neuroinflammation lesions.