This study evaluated the antibacterial efficacy and growth-promoting potential of Moringa oleifera and Thymus vulgaris methanolic extracts in broiler chickens challenged with Escherichia coli O78. In vitro antibacterial screening using agar well diffusion and disc diffusion assays revealed that ciprofloxacin exhibited the strongest inhibitory effect, followed by tetracycline and enrofloxacin, whereas among plant extracts, T. vulgaris was more effective than M. oleifera. The optimal combination (M100T150; 100 mg M. oleifera + 150 mg T. vulgaris) produced the largest inhibition zones against E. coli strains. For the in vivo trial, 540 Ross-308 broiler chicks were distributed into six treatment groups in a completely randomized design and reared for 42 days. Parameters assessed included growth performance, carcass traits, gut pH, ileal microbial counts, and intestinal histomorphology. Results showed that E. coli challenge significantly reduced feed intake, weight gain, carcass yield, and villus integrity while increasing FCR and E. coli counts (p < 0.05). Addition of plant extracts, particularly M100T150, significantly improved weight gain, FCR, Broiler Performance Efficiency Factor (BPEF), and Broiler Farm Economy Index (BFEI) compared to the positive control (p < 0.05). Extracts reduced duodenal and jejunal pH (p < 0.001), suppressed E. coli counts (p = 0.003), and enhanced Lactobacillus populations (p = 0.0004). Histological analysis revealed that extract-supplemented groups had greater villus height and surface area with shallower crypts than the positive control, indicating restoration of gut integrity. These findings suggest that methanolic extracts of M. oleifera and T. vulgaris, particularly in combination, can serve as natural alternatives to antibiotics in broiler production under pathogenic challenge.