Wnt4 has been shown to promote the recovery of odontogenic differentiation of dental pulp stem cells under inflammatory conditions, but its role in inflammation and apoptosis of pulpitis remains to be elucidated. Lipopolysaccharide (LPS) (10 µg/ml) was applied to treat the human dental pulp cells (HDPCs) for 24 h. Western blotting measured the expressions of inflammatory cytokines and apoptosis-related proteins. Cell apoptosis was measured by flow cytometry. The level of Wnt4 was evaluated by reverse transcription-quantitative PCR and western blotting. The results indicated that LPS could promote inflammatory response and apoptosis in HDPCs and downregulated Wnt4 expression was found in LPS-HDPCs. Overexpression of Wnt4 ameliorated cell inflammatory response and apoptosis, presented by reduced expressions of IL-8, IL-6, TNF-α, IL-1β, Bax, cleaved-caspase 3 and enhanced Bcl-2 expression as well as decreased apoptosis rate. Moreover, overexpression of Wnt4 reduced the phosphorylation levels of IKK2, IκBα and p65 proteins upregulated by LPS. Finally, overexpression of IKK2 reversed the effects of Wnt4 on inflammation and apoptosis of LPS-HDPCs and NF-κB inhibitor reversed the effect of IKK2 overexpression in LPS-HDPCs. Wnt4 inhibited LPS-triggered inflammation and apoptosis in HDPCs via regulating the IKK/NF-κB signaling pathway, which provided a new viewpoint for understanding the pathological mechanism of pulpitis.