Abstract Salivary hypofunction is a common complication in patients with head and neck cancers following radiotherapy (RT). RT‐induced inflammation in salivary gland cells leads to apoptosis and fibrosis. Artesunate (ART) is a bioactive compound with anti‐inflammatory and anti‐fibrosis properties. This study aimed to investigate the protective effects of ART on X‐ray‐induced injury of submandibular gland (SMG) epithelial cells in rats. Second‐generation SMG epithelial cells were randomly divided into five groups: natural control group (NC), irradiated group (IR), and irradiated groups treated with ART at concentrations of 5, 10, and 20 μM. Cells were harvested 48 h postirradiation for analysis. The results demonstrated that ART attenuated the damage to AQP5, a crucial indicator of salivary gland function, as evidenced by the decreased expression of AQP5 at both mRNA and protein levels. Additionally, ART decreased the expression of inflammatory cytokines: IL‐6 and TNF‐α. TUNEL staining revealed reduced apoptosis in the ART groups, particularly the IR + 10 μM group. RT‐PCR and Western blot analysis of apoptosis cytokines Bax/Bcl‐2 and Caspase‐3 confirmed these findings. Furthermore, ART inhibited the expression of NF‐κB at both mRNA and protein levels. In conclusion, these results suggest that ART may reduce inflammation and apoptosis in SMG epithelial cells following radiation by inhibiting the NF‐κB pathway.