Transition period is a very critical period for buffaloes that extends three weeks before calving up to 3 weeks after calving. Few published papers about the changes in Egyptian buffaloes' metabolic and hematologic parameters are reported at this period. The current study was designed to investigate the physiological variations in hematological and some metabolic parameters in Egyptian buffaloes during transition period. Fifteen pluriparous pregnant Egyptian buffaloes were subjected to weekly blood sampling at 21 days before calving (-21), at calving day (0), and at 21 days post calving (+21). Complete blood picture (CBC) was determined in whole blood samples. Leptin, non-esterified fatty acids (NEFA), total cholesterol (TC), high density lipoprotein (HDL), triglycerides (TG), blood glucose values, albumin, alanine aminotransferase (ALT), and blood urea nitrogen (BUN) were analyzed. Levels of malondialdehyde (MDA) and nitric oxide (NO) were also estimated. Hematological analysis revealed significant (P<0.05) increase in total leukocytes count accompanied with neutrophilia and monocytosis during postpartum period. Serum NEFA, TC, ALT, BUN, MDA and NO were significantly increased during postpartum period while leptin, TG and albumin were significantly (P<0.05) declined than prepartum period. From these results, the physiological adaptations of the buffaloes under the study suggest that negative energy balance during postpartum period needs efficient management to prevent metabolic disorders and their associated diseases.