The rapid increase in antibiotic resistance poses a global threat to public health, necessitating the development of effective antimicrobial alternatives. This study compared an indigenous probiotic mix containingLactobacillus reuteriand two strains ofEnterococcus faeciumto a commercial probiotic blend ProtexinRon the growth performance, mortality rate, histomorphology, serum immunoglobulins, and intestinal microflora of broiler chickens challenged with two multi drug resistantSalmonellaserovars, Typhimurium and Enteritidis. Two hundred and forty day-old broiler chicks were randomly assigned to six treatment groups for 4 weeks: the treatment groups were; birds continuously supplemented with only indigenous probiotic strains (108CFU/mL) (IPRO-); birds challenged withSalmonellaserovars 106(CFU/mL) (PC+); birds continuously supplemented with indigenous probiotic strains and challenged withSalmonellaserovars (IPRO+); birds supplemented with ProtexinRand challenged withSalmonellaserovars (CM+); birds supplemented with only ProtexinR(CM-); and birds with noSalmonellachallenge or probiotics (negative control; PC-). The results revealed that IPRO- diets significantly improved feed conversion ratio (FCR) and increased body weight (BW) (P≤ 0.05). No effect of probiotic treatments was observed on IPRO- and CM- on relative organ weights as compared to the negative control (PC-). TheSalmonella- challenged group PC+ had the highest (20%) mortality rate and lowest BW. The IPRO- had significantly lower FCR (1.55) compared to PC- (1.86) and PC+ (1.95). The broilers in the IPRO- group showed significantly increased serum concentrations of IgA and IgG relative to both control groups (P≤ 0.05). Morphological analysis of the ileum revealed significant increases (P≤ 0.05) in the villus height and villus height/crypt depth in birds fed IPRO- compared with the PC+. CecalLactobacillusandEnterococcuscounts were the highest (P≤ 0.05) andSalmonellacounts were the lowest (P≤ 0.05) in the IPRO- group compared to theSalmonellainfected group PC+. These results indicated that indigenous probiotic strainsLactobacillus reuteriandEnterococcus faeciumcan be an effective and low-cost alternative compared to commercial probiotics in the Pakistan poultry industry.