Osteosarcoma (HOS cells) and fibrosarcoma (HT1080 cells) were used to investigate the anti-cancer effect of arsenic trioxide (ATO) and the underlying mechanisms in vitro and in vivo. We found that ATO treatment enhanced the percentage of apoptosis and autophagy in HOS and HT1080 cells through increasing the expression of ER stress-associated protein IRE1 and led to induction of LC3-II and cleaved-caspase-3. ATO significantly decreased the phosphorylation of Akt and mTOR and increased the phosphorylation of AMPK, p38, and JNK in HOS and HT1080 cells. Combined treatment of ATO and MG-132 showed synergistic effect through induction of apoptosis and autophagy in HT1080 cells. In in vivo study, the combined treatment significantly reduced the tumor volume in SCID mice that had received a subcutaneous injection of HT1080 cells. Thus, a combination of ATO and proteasome inhibitor could be a new potential therapeutic strategy for the treatment of fibrosarcoma.