This study evaluated the effectiveness of hyperosmotic sodium bicarbonate (HSB) in ameliorating strong ion difference (SID) and correcting acidemia in experimentally induced buffalo neonatal diarrheic calves. For that purpose, 18 buffalo calves of 14-17 days of age were reared. Salmonella broth was introduced orally to the calves for induction of diarrhea. Calves were then randomly assigned to one of the three treatment regimens i.e., group A was treated with normal saline solution (NSS; 0.9% NaCl) @ 60 mL/Kg BW, IV once, group B was administered with hypertonic saline solution (HSS; 7.5% NaCl) @ 5 mL/Kg BW, IV once, while group C administered with HSB (8.4% NaHCO₃) @ 5 mL/Kg BW, IV once. All groups were additionally treated with ciprofloxacin @ 7 mg/Kg BW, IV bid and flunixin meglumine @ 2 mg/Kg BW, IV tid for five consecutive days. Efficacy of HSB was assessed through clinical parameters, hematological parameters, blood D- and L-lactates, acid-base variables, and serum electrolytes. All parameters were observed at different time points. Group C showed higher survival than other groups. HSB infusion to neonatal calves of group C significantly (P<0.05) reduced blood D-lactate level and ameliorated SID variables than other groups A and B. It is concluded that administration of HSB is highly effective in alkalinizing diarrheic calves with strong ion acidosis thus efficiently reversing metabolic acid-base balance in Salmonella-induced neonatal diarrhea in buffalo calves.