Foot rot is a contagious disease caused by F.necrophorum. It is responsible for economic losses in dairy farming. Studies on foot rot in dairy cows are focused on the isolation and identification of pathogens and treatment methods. Few studies have reported inflammatory changes in tissues and regulatory mechanisms following infection. Here, the effects of F.necrophorum infection on the skin explants and skin fibroblasts between the toes of cattle were analyzed using histopathology and other techniques. F.necrophorum infection increased the epidermal thickness and number of hair follicles and sebaceous glands. Other skin appendages exhibited varying degrees of necrosis, and a significant infiltration of inflammatory cells was noted in the interdigital skin explants. The expressions of pro-inflammatory cytokines (IL-1β and TNF-α) and key genes in the inflammatory signalling pathway (TNFR1 and NF-κB p65) were elevated. Treatment with the TNFR1 inhibitor CAY10500 reduced inflammatory cell infiltration and alleviated TNFR1 and p65 expression. An inflammatory cell model was established using different proportions of F.necrophorum to infect BDF cells. F.necrophorum infection significantly inhibited the proliferation and viability of BDF cells and enhanced the expression of TRADD, TRAF2, TNF-α, and IL-18. CAY10500 reduced the F.necrophorum infection-induced inflammatory response and induced inflammatory responses in interdigital skin explants and BDF cells by inhibiting the TNF-α/TNFR1/NF-κB signaling pathway. In summary, these findings provide new insights into the mechanism of inflammatory responses in dairy cows with foot rot.