This research aimed to examine the possible effectiveness of treatment with a freshly formulated new probiotic versus Phaleria macrocarpa leaves extract indicated by the histopathological changes occurred to the colon of the immunocompromised New Zealand White (NZW) rabbits. The study included 40 rabbits, divided into 4 groups. Three of the groups were fed with the immunosuppressive medication (azathioprine, 500 mg/kg/day) to be immunocompromised, Group B was treated with P. macrocarpa extract, Group Ctreated with our developed probiotic, and the group D left untreated as a positive control, Group A regarded as control negative. The duration of immunocompromising drug induction was set as 14 days; and the period of treatment was set for another 14 days. Distinctly, the treated rabbits were showing improvements of healing processes compared to non-treated, where the signs of lack of normal mucous folds, different degrees of mucosal edema and congestion, submucosal hemorrhage, accumulative score of gross colon morphology and major severe lesions of the colon tissue of the non-treated were significantly improved in the probiotic treated, as well as, P. macrocarpa treated groups. As a conclusion, the results indicated that uptake of the formulated probiotic could strengthen rabbits’ immune responses of the immunoco-mpromised rabbits significantly (both the specific and non-specific responses) and retain the weakened colon tissues (caused by the immunosuppressant drug). These findings are recommended to be used in future for development of promising commercial supplements to mitigate the medical risks that comes with immunosuppressant medications currently given to animals or human patients under certain circumstances.