BACKGROUND AND AIM: The transition period is extremely critical for pregnant producing animals. However, there is very limited research on the metabolic and immunological changes in Egyptian water buffalo cows during the transition period. Therefore, this study was conducted to investigate the immunometabolic changes occurring during the transition period in Egyptian water buffalo cows. MATERIALS AND METHODS: A total of 50 multiparous pregnant Egyptian water buffalo cows were subjected to weekly blood sampling 3 weeks before calving and 3 weeks after calving and on the day of parturition to determine the complete blood count, including red blood cell count, total leukocyte count (TLC), differential leukocyte count, hemoglobin level, and packed cell volume (PCV). Some selected serum biochemical and immunological parameters were analyzed, including serum glucose, beta-hydroxybutyric acid (BHBA), non-esterified fatty acids, triglycerides, high-density lipoprotein, low-density lipoprotein (LDL), very LDL (VLDL), cholesterol, total protein, albumin, globulin, creatinine, blood urea nitrogen (BUN), aspartate aminotransferase, alkaline phosphatase, alanine transaminase, gamma-glutamyl transferase, Haptoglobin, and C-reactive protein and the pro-inflammatory cytokines interleukin ß1, interleukin 6 (IL-6), and tumor necrosis factor-alpha. All data were statistically analyzed using the IBM Statistical Package for the Social Sciences statistics software. RESULTS: The neutrophil count showed a statistically significant increase at 2 weeks preparturition. There was also a significant increase in PCV, TLC, neutrophil count, and IL-6 and TNF-a level at the time of parturition and even at 2 weeks post parturition, except PCV that returned to normal levels in the 1st week post parturition. BHBA and BUN levels were increased significantly in the 2nd and 3rd weeks postcalving. Serum creatinine and VLDL levels were decreased significantly at the time of parturition, and VLDL levels showed a significant decrease even till the 3rd week postcalving, whereas creatinine levels gradually returned to the pre-calving levels in the 3rd week postcalving. Other parameters showed no significant changes. CONCLUSION: The most important immunometabolic changes occur in the first 2 weeks post parturition in Egyptian water buffalo cows, which exhibit a potent, remarkable physiological adaptation achieved by their functional liver, which can help the animal overcome the stressful conditions during the transition period.