Strains of live Saccharomyces cerevisiae yeast have exhibited probiotic effects in ruminants. This study investigated the effects of the dietary yeast supplement, S. cerevisiae (Yea-Sacc¹⁰²⁶), on primiparous (PP) and multiparous (MP) Egyptian buffaloes in early to mid-lactation. Lactating buffaloes were fed either a basal total mixed ration (TMR, control; 4 PP and 8 MP) or the basal TMR plus 10 g Yea-Sacc¹⁰²⁶ per buffalo cow per day (yeast; 4 PP and 8 MP). The feeds were given from 15 days prepartum to 180 days postpartum. Feed intake, body weight, and milk yields (MY) were recorded, and milk and blood samples were collected for analyses. Feces were collected from days 45 to 47 during early lactation and from days 90 to 92 during mid-lactation to determine apparent digestibility of dry matter (DM), organic matter (OM), crude protein (CP) and crude fiber (CF). Energy corrected milk yield (ECM), feed conversion, and energy and nitrogen conversion efficiency were calculated. Yeast treated MP buffaloes consumed more DM (P ≤ 0.041) and CP than the untreated control group. Apparent digestibility of DM and OM were significantly greater at mid-lactation for treated versus control group (P = 0.001). Crude fiber digestibility was greater in MP than in PP buffaloes (P = 0.049), and yeast supplemented MP cows had a greater CF digestibility than control MP buffaloes at mid-lactation (P = 0.010). Total blood lipids decreased after yeast supplementation (P = 0.029). Milk yields, ECM, fat and protein yields increased for yeast treated MP buffaloes (P ≤ 0.039). The study concluded that the response to yeast supplementation in buffalo cows is parity dependent. Multiparous buffaloes respond to yeast supplementation with an increased DM intake and CF digestibility without significant weight gains, allowing a greater ECM yield with less fat mobilization. Supplementing buffaloes with yeast culture may increase milk production in early lactation and results in a more persistent milk production during mid-lactation. Feed conversion and energy and nitrogen conversion efficiency may be increased with the use of yeast supplementation in Egyptian buffaloes.