Colitis-associated colorectal cancer serves as a prototype of in ammation-associated cancers which is linked with repeated cycles of in ammation and DNA repair de cits. Several preclinical and clinical data reported that aspirin has chemo preventive effect in colorectal cancer and is associated with dose dependent side effects. Further, it has been reported that zinc supplementation improves the quality of life in patients undergoing chemotherapy by alteration of colonic cancer cell gene expression. However, explication of the detailed molecular mechanisms involved in combined administration of aspirin and zinc mediated protection against the colitis associated colorectal cancer deserves further investigation. For the induction of colitis associated colorectal cancer, male BALB/c mice were administered 1, 2dimethylhydrazine dihydrochloride (DMH) 20 mg/kg/bw thrice, before the initiation of every DSS cycle (3%w/v in drinking water). One week after the initiation of DSS treatment, aspirin (40 mg/kg; p.o.) and zinc in the form of zinc sulphate (3 mg/kg; p.o.) was administered for 8 weeks. Combination of aspirin and zinc as intervention signi cantly ameliorated DAI score, myeloperoxidase activity, histological score, apoptotic cells and protein expression of various in ammatory markers including nuclear factor kappa light chain enhancer of activated B cells (NFκBp65), cycloxygenase -2 (COX-2), interleukin-6 (IL-6); proliferation markers such as proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription 3 (STAT3) expression signi cantly decreased and antioxidant enzymes nuclear factor erythroid 2-related factor 2 (Nrf-2), metallothionein, catalase and superoxide dismutase (SOD) signi cantly increased as evaluated by immunohistochemistry and western blot analysis.