Tissue factor (TF) is a cell surface protein that plays a role in blood clotting but is also commonly expressed in many cancers. Recent research implicated TF in cancer proliferation, metastasis, angiogenesis, and immune escape. Therefore, TF can be considered a viable therapeutic target against cancer. Herein, we developed and tested a TF-targeted near-infrared photoimmunotherapy (NIR-PIT) as a potential treatment for several types of cancer. Tisotumab, a TF antibody, was conjugated to IR700. The efficacy of TF-targeted NIR-PIT was investigated using multiple cancer cell lines (A431; epidermoid carcinoma, HPAF-II; pancreatic adenocarcinoma, HSC-2; oral carcinoma, HT1376-luc; bladder carcinoma, MDAMB231; breast adenocarcinoma, and SKOV3-luc; ovarian serous cystadenocarcinoma) in vitro. In vivo, the efficacy of TF-targeted NIR-PIT was evaluated in HPAF-II and A431 xenograft mouse models. Pathologic changes in these tumors after NIR-PIT were evaluated in these tumor models. All cancer lines demonstrated TF expression in vitro and in vivo. Additionally, TF expression was documented to localize to cancer cells in tumors. In vitro, TF-targeted NIR-PIT caused cell death in a light dose-dependent manner. In vivo, TF-targeted NIR-PIT suppressed tumor growth and improved survival rates compared to controls. Furthermore, in vivo NIR-PIT showed histological signs of cancer cell damage, such as cytoplasmic vacuolation, nuclear dysmorphism, and extracellular leakage of LDHA consistent with cell death. In conclusion, TF-targeted NIR-PIT holds promise as a treatment for multiple cancer models expressing TF, spanning multiple cancer types.