Objective: Curcumin (Cu) exhibits antitumor and anti-inflammatory activity in oral carcinogenesis but has limited clinical translation due to poor bioavailability, which piperine (Pip) can improve. This study evaluated the antitumor and immunomodulatory effects of intraperitoneal Cu-Pip therapy, given for 2 or 4 weeks, in a DMBA-induced hamster buccal pouch carcinogenesis model, focusing on programmed death ligand-1 (PDL-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression. Materials and methods: Twenty male Syrian golden hamsters were allocated to a negative control (A1), a DMBA-only positive control (A2), and two DMBA-exposed groups treated intraperitoneally with Cu (80 mg/kg) and Pip (1 mg/kg) daily for 2 (A3) or 4 weeks (A4). Body weight, tumor area, leukocyte counts, serum IL-10/TNF-α, -histopathological grade, and intratumoral PDL-1 and CTLA-4 expression were compared. Results: A3 and A4 groups showed significant reductions in body weight and tumor area relative to A2. Histopathology shifted from deeply invasive, moderately differentiated carcinoma in A2 to well-differentiated, superficially invasive carcinoma in A4. IL-10 and TNF-α were extremely significantly elevated in A2 relative to A1. TNF- α showed continuous elevation in A3 and A4, while IL-10 declined extremely significantly in A3 and A4 relative to A2. Neutrophilia and lymphopenia in A2 were partially reversed by treatment. CTLA-4 levels were extremely significantly reversed in A3 and fell extremely significantly in A4 relative to A2. PDL-1 declined significantly only in A4. Conclusions: Intraperitoneal Cu-Pip therapy reduced tumor burden and histopathological aggressiveness, with duration-dependent changes in the expression of cytokines and immune checkpoints. This suggests that there are immunomodulatory effects contribute to its antitumor activity, warranting further investigation.