Mitomycin C (MMC), a chemotherapeutic agent in breast cancer treatments, inhibits tumor growth through DNA cross-linking and breaking, but it has severe side effects. Here we examined whether and how curcumin reduced the side effects of MMC. We found that combination treatment with MMC and curcumin reduced tumor weight by 70% and 36% compared with saline and curcumin-treated groups, respectively. The combination treatment reduced weight loss and improved kidney function and bone marrow suppression compared with MMC treatment alone. Moreover, the combination treatment inhibited glucose regulatory protein (GRP58)-mediated DNA cross-linking. The combination treatment inhibited GRP58 through the ERK/p38 MAPK pathway. In conclusion, the current study provided evidence that MMC and curcumin combination treatment reduced MMC side effects by inhibiting GRP58-mediated DNA cross-linking through the ERK/p38 MAPK pathway.