Triple negative breast cancer is the most malignant subtype of breast cancer and current treatment options are limited. Radiotherapy is one of the primary therapeutic options for patients with TNBC. In this study, we discovered that the E3 ubiquitin ligase, HECTD3, promoted TNBC cell survival after irradiation. HECTD3 collaborated with UbcH5b to promote p62 ubiquitination and autophagy while HECTD3 deletion led to p62 accumulation in the nucleus in response to irradiation, thus inhibiting RNF168 mediated DNA damage repair. Furthermore, the HECTD3/UbcH5b inhibitor, PC3-15, increased the radiosensitivity of TNBC cells by inhibiting DNA damage repair. Taken together, we conclude that HECTD3 promotes autophagy and DNA damage repair in response to irradiation in a p62-denpendent manner, and that inhibition of the HECTD3-p62 axis could be a potential therapeutic strategy for patients with TNBC in addition to radiotherapy.