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Abstract Background Colorectal cancer has been found to be attenuated either with prophylactic manipulation of gut microbiome with probiotics or celecoxib, a non-steroidal anti-inflammatory drug mainly by suppressing early pro-carcinogenic markers in various experimental studies. Therefore, the present study was designed to assess the prophylactic potential of combinatorial administration of probiotics (Lactobacillus rhamnosus GG, Lactobacillus acidophilus) and celecoxib in experimental colon carcinogenesis. Methods Six groups of Spraugue Dawely rats received probiotics L.rhamnosus GG or/and L.acidophilus in combination with celecoxib one week prior to the inducement of tumor by 1,2-dimethylhydrazine (DMH) and the treatment continued for 18 weeks. Prophylactic potentials of probiotics and celecoxib were determined by employing various methods such as tumor incidence, tumor burden, tumor multiplicity, apoptosis, caspase activity, expression of proto-oncogene K-ras and tumor suppressor p53 gene in colonic tumors. Results Interestingly, it was found that one week prior supplementation of both probiotics and celecoxib reduced tumor burden, tumor multiplicity, down-regulated the expression of anti-apoptotic Bcl-2, proto-oncogene K-ras and up-regulated pro-apoptotic Bax as well as tumor suppressor p53 in L.rhamnosus GG + celecoxib+DMH animals compared with counter controls and DMH-treated. Conclusions It can be concluded that such combinatorial approach may be useful in reducing the burden and severity of disease in highly susceptible individuals but needs to be validated clinically.