Nitrogen mustard (NM) belongs to vesicant agents. Blisters are one of the important characteristics of NM skin damage. It is urgent to further elucidate the mechanism and develop effective countermeasures for the skin damage induced by NM. The endoplasmic reticulum (ER) is an important intracellular organelle, playing an important role in maintaining cellular homeostasis. In this study, we explored the role of endoplasmic reticulum stress (ERS) and the protective effect of asiatic acid (AA) in the HaCaT cells induced by NM. It was found that the key regulatory proteins of ERS, such as glucose regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), inositol requiring enzyme 1 (IRE1), Phospho-IRE1 (pIRE1), and TNF receptor associated factor 2 (TRAF2) were increased respectively in HaCaT cells exposed to NM compared with those of the control group, showing an increasing trend with the increase of NM exposure concentration and exposure time. Additionally, the protein expression of Caspase-3 and the Cleaved-Caspase-3 was also increased by NM in HaCaT cells, resulting in the apoptosis of HaCaT cells. Meanwhile, the content of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) was also increased in HaCaT cells exposed to NM. Further study showed that AA pretreatment could decrease the protein expression of GRP78, XBP1 and IRE1, pIRE1, TRAF2, Caspase-3, and Cleaved-Caspase-3. And moreover, AA also could reduce the content of TNF-α and IL-6. Overall, the present study showed that AA played an important protective effect in HaCaT cells exposed to NM through the inhibition of the ERS-induced apoptosis and inflammatory response.