Phosphodiesterase 10A (PDE10A) is a dual-substrate phosphodiesterase that is highly expressed in the striatal complex. PDE10A is an important target for the treatment of ganglion dysfunction and neuroinflammation-related diseases, but its possible impact on traumatic brain injury (TBI) is still unclear. This study aims to investigate the protective effects of inhibiting PDE10A on neuroinflammation post-TBI injury and its possible molecular mechanism. The expression of PDE10A in rats and HT22 cells was determined by Western blotting. The neurological dysfunction of these rats was detected by Nissl staining, hematoxylin-eosin (HE) staining, and Morris water maze test. The activity of HT22 cells was measured by MTT. The findings of this study suggest that PDE10A is highly expressed in the brain tissue of TBI rats and HT22 cells induced by mechanical injury. Inhibition of PDE10A reduces the expression of interleukin-1β (IL-1β) and interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) in HT22 cells induced by mechanical injury to inhibit cell apoptosis. Simultaneously, inhibition of PDE10A in TBI rats reduces the time to find a visible platform in the same pool, while cAMP/PKA activator treatment alleviates all of the abovementioned phenomena. Additionally, it is further confirmed that inhibition of PDE10A activates the cAMP/PKA pathway and downregulates the expression of NRLP3. These findings demonstrate that inhibition of PDE10A exerts neuroprotection by inhibiting apoptosis and inflammation following TBI, at least partially by the cAMP/PKA/NLRP3 pathway.Copyright © 2022 Jin Huang et al.