This study was proposed to highlight the impact of dietary Spirulina platensis (SP) supplementation in alleviating the deterioration effect of Escherichia coli (EC) on the growth performance, redox biomarkers, immune reaction, and hindgut microbial counts and acidosis in broiler chickens. Four hundred Cobb500, one-day-old, broiler chickens were deposited in battery cages (10 chicks per cage). The chicks were distributed into totally randomized 2 × 2 factorial treatments (10 replicate cages per treatment) from the day 22 to the day 42 of age. Birds of two of the groups were fed on a basal diet without SP supplementation (-SP groups), while birds of the other two groups were fed on a basal diet supplemented with 10 g/kg SP (+SP groups). At day 36th of age, birds in one of the -SP and +SP groups were challenged by an intraperitoneal (i.p.) injection with 107 CFU/bird EC (O157:H7 strain) in 0.5 mL sterilized saline (+EC groups), whereas the other non-challenged groups were i.p. injected with 0.5 mL saline only (-EC groups). The current study results indicated that the boilers challenged with EC had a significant (p < 0.05) lower performance, poor antioxidant activity, immunosuppression, and higher numbers of pathogenic bacteria in the intestine when compared with the non-challenged birds. Dietary SP inclusion enhanced (p < 0.05) broiler growth, antioxidant activity, immune response, and intestinal beneficial bacteria and acidosis. Moreover, SP alleviated the reduction in all these parameters after exposure to EC infection. Therefore, diets containing 10 g/kg SP could be used as a promising approach to maximize broilers' production and support their health, particularly when challenged with EC infection.