To date, the mortality of tongue squamous cell carcinoma (TSCC) is still high, COX‐2 is highly expressed in the head and neck cancers, and targeting COX‐2 is a potential treatment for TSCC. Herein, a series of novel carborane compounds based on COX‐2 inhibitors have been developed for the effective treatment of TSCC by boron neutron capture therapy (BNCT). Notably, the compound 1 had high COX‐2 selectivity and low cytotoxicity against CAL27 cells. Meanwhile, the compound 1 had higher selectivity and uptake of CAL27 cells compared to the positive control group sodium borocaptate (BSH). The apoptosis of CAL27 cells treated with the compound 1 during BNCT was significantly induced by breaking DNA double strands and generating excess reactive oxygen species, and the proliferation of cancer cells was inhibited by down‐regulating the expression of cytokines associated with phosphatidylinositide 3‐kinases/protein kinase B (PI3K/Akt) and mitogen‐activated protein kinases (MAPKs) signaling pathways in BNCT. Thus, the carborane compounds based on COX‐2 inhibitors have the potential to effectively treat tongue squamous cell carcinoma through BNCT.