Pyroptosis contributes to the neuronal damage that occurs during epilepsy. Calcium-activated neutral protease (calpain) dissociates cysteinyl aspartate specific proteinase-1 (caspase-1, cas-1) from the cytoskeleton, and the activated cas-1 is responsible for the production of N-terminus of gasdermin D (N-GSDMD), the final executor of pyroptosis. Blocking transient receptor potential vanilloid 4 (TRPV4) can reduce neuronal injury in temporal lobe epilepsy (TLE) model mice. This study investigated the role of TRPV4 in pyroptosis during TLE. In the hippocampus of pilocarpine-induced status epilepticus (PISE) mice, the ratio of inactive calpain 1 protein level to its total protein level (inactive/total calpain 1) significantly decreased, while the ratio of inactive calpain 2 protein level to its total protein level remained unchanged. The protein levels of NLRP3, cleaved cas-1 (c-cas-1), interleukin (IL)-1β, and N-GSDMD increased, with more GSDMD-immunofluorescence-positive (GSDMD+) cells and fewer surviving pyramidal neurons observed in the hippocampus of PISE mice. Calpain inhibition with MDL-28170 reversed these changes, except for the elevated NLRP3 levels. Inhibitors targeting NLRP3 (MCC950) and cas-1 (Ac-YVAD-cmk) blocked the increase in c-cas-1, IL-1β, and N-GSDMD levels in the hippocampus of PISE mice. TRPV4 inhibition via HC-067047 increased the inactive/total calpain 1 ratio, decreased NLRP3, c-cas-1, IL-1β, and N-GSDMD protein levels, reduced GSDMD+ cells number, and improved pyramidal neuron survival in the hippocampus of PISE mice. Conversely, TRPV4 activation with GSK1016790A decreased the inactive/total calpain 1 ratio, elevated NLRP3, c-cas-1, IL-1β, and N-GSDMD levels, and increased GSDMD+ cells number in the hippocampus. In the hippocampus of GSK1016790A-injected mice, the inactive/total calpain 1 ratio was increased by MDL-28170, and c-cas-1, IL-1β, and N-GSDMD protein levels were markedly attenuated by MDL-28170, MCC950, and Ac-YVAD-cmk, respectively. In conclusion, TRPV4 inhibition mitigates pyroptosis in PISE mice by downregulating the calpain 1-NLRP3/cas-1-GSDMD pathway, ultimately reducing neuronal damage.