Transferrin receptor (TfR) has been used as a target for antibody-based therapy of cancer. Combining anti-TfR antibodies with chemotherapeutic drugs shows potential as one of the strategies for cancer therapy. In this study, we investigated the effects of anti-TfR monoclonal antibody 7579 alone or in combination with chemotherapeutic drugs (5-fluorouracil or doxorubicin) on non-hematopoietic tumor cells (HepG2 and MCF-7) in vitro. We found that 7579 mAb alone could dramatically down-regulate surface TfR expression on tumor cells. Consequently, marked S phase arrest and apoptosis were observed in 7579 mAb-treated tumor cells. In combination with 5-fluorouracil or doxorubicin, 7579 mAb enhanced the growth inhibitory effects of chemotherapeutic drugs on tumor cells. Results of 7AAD/Annexin V staining demonstrated that 7579 mAb enhanced the cytotoxic effects of chemotherapeutic drugs on tumor cells by mainly promoting tumor cell necrosis. Using the median-effect/combination-index isobologram method, we further evaluated the nature of 7579 mAb/chemotherapeutic drug interactions. Synergistic interaction was observed for 7579 mAb combined with 5-fluorouracil whereas additive efficacy was observed for 7579 mAb plus doxorubicin. Our study provided the basis to further develop 7579 mAb-containing chemoimmunotherapy for non-hematopoietic malignancies.