Swiss albino mice in three groups (control, experimental I and experimental II) of 60 each were fed staple diet (control), diet composed with 2% pan masala plain (PMP) and its blend (tobacco-PMT) for a period of up to 70 weeks with intermittent postmortem at 16, 56 and 70 weeks for assessing histological changes of the gut histopathology of mice. Mice of experimental groups I and II showed progressive advancement of structural changes of stomach during the study period. Fibrosis, thickening of prickle cells and also horney layered cells indicating lesions of acanthosis and hyperkeratosis initially and later prominently ulcers and papillomas which transformed into a peptic tumor occured. Spleen was found enlarged in mice fed with PMT. Animal feeding, hygiene, exploration and environmental care and health protocols were as per the standard guidelines and approved by National Institute of Occupational Health ethical committee. Here, chronic exposure of mice has been consistent in respect of feed and environment, unlike habitual PM users whose consumption is inconsistent depending on the body demand and choice on the variety of the blended PM product. This study endorses generating critical clinically designed case control, cohort data for awareness programs and PM substitutes as well as treatment to PM addicts.