So far, there has been scarce information about the status of immunoglobulins (Ig) and the gene expression of inflammatory cytokines in buffaloes showing digestive troubles. The purpose of the present study was to explore the modulation of gene expression of some immune-inflammatory markers in buffaloes suffered from various digestive disorders. For this reason, 50 native breed water buffaloes were studied. Forty of these buffaloes showed various symptoms of digestive disorders and were allocated into 4 groups of equal sizes (group 1: uncategorized stomatitis; group 2: acute traumatic reticuloperitonitis [TRR]; group 3: acute rumen impaction; and group 4: undifferentiated enteritis). Ten apparently healthy buffaloes were randomly selected and considered as a control group. RNA was firstly extracted from the whole blood then a reverse transcription kits was used to convert the RNA to cDNA. Real-time PCR was used to measure the expression of mRNAs of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor (TNF)-α, IgG, and IgA, while glyceraldehyde-3-phosphate dehydrogenase (GAPDH) used as an internal reference. The results of real-time PCR revealed a significant (P ≤ 0.05) upregulation of the gene expression of IL-1β, IL-6, IL-10, and TNF-α in blood of diseased buffaloes compared with those of controls. Animals showing acute TRP had peak values of both IL-6 and IL-10; while those exhibiting enteritis and rumen impaction had the highest values of IL-1β and TNF-α, respectively. The results of qPCR also revealed a significant (P ≤ 0.05) downregulation of both IgG and IgA gene expression in blood of all diseased buffaloes compared with controls. The lowest values of both genes were recorded in buffaloes showing acute TRP. The results herein suggest that the tested genes could have a pivotal role in the pathophysiologic mechanism of the underlying diseases.