Introduction: Oral squamous cell carcinoma (OSCC) shows unsatisfied survival rate which remains not changed over the last years. Thymoquinone (TQ) is a phyto­chemical, and many studies proved its promising therapeutic effect against OSCC. Gold nanorod (GNR) is a photothermal agent, has an efficient near-infrared heat conversion and induces ablation of solid tumors. The combination of photothermal therapy (PTT) and chemotherapy can enhance synergistic effects that markedly exceed the sum of individual treatments alone. Aim: this study aimed to evaluate the effect of combined photothermal and nano chemotherapy in treatment of induced oral squamous cell carcinoma in hamsters. Material and Methods: In the present study, the combined drug GNR/NTQ loaded on (poly) (lactic-co-glycolic acid) (PLGA) was prepared. The targeting agent, folate or folic acid (FA), was conjugated to the prepared nanoparticles. The therapeutic ac­tivity of the drug against chemically-induced OSCC in hamster buccal pouches was evaluated by clinical observations, tumor volume analysis, histopathological alterations and blood analysis. Results: The combined drug (GNR/NTQ/PLGA/FA/laser) had the highest therapeutic activity compared to individual treatments. It significantly ablated and regressed tumor size in chemically-induced OSCC in the hamster model as com­pared to the other preparations; GNR/NTQ/PLGA/FA without laser, GNR/ PLGA/FA/ laser and NTQ/PLGA/FA/laser. Conclusion: Compared to the single PTT or nanoche­motherapy, the combined PTT/nanochemotherapy with laser provides better therapeu­tic effects against OSCC