Single or combined essential oils (EOs), and organic acids (OAs) blends were used as continuous drinking water (DW) treatment for protection against Clostridium perfringens (C. perfringens) experimental infection in chickens. Random assignment of 185 one-day-old, commercial broiler chicks into 6 groups (30 chicks/group in 3 replicates) arranged as follows: a non-infected group (G1), C. perfringens infected (G2). In contrast, G3, and G4 were infected with C. perfringens and continuously supplemented with EOs, and OAs, respectively in DW from day 1. Chickens in G5 were challenged with C. perfringens and had a mixture of both products continuously in DW from day 1. At the same time, the birds of G6 were challenged with C. perfringens and treated with amoxicillin. All groups were fed a basal diet. Our results showed that combined EO and OA blends were more effective in ameliorating the devastating effects of C. perfringens in broilers than single treatments. In the infected-treated groups, the growth performance represented by body weight gain, and feed conversion ratio were improved (p < 0.05), intestinal lesion scores, and C. perfringens count were significantly low. Also, the intestinal histopathology and biochemical profile were improved. In addition, iNOS and IL-1β (pro-inflammatory cytokines) levels were significantly down regulated while IL-10 (anti-inflammatory cytokine) was increased (p < 0.05). Furthermore, the phagocytic activity was significantly (p < 0.05) enhanced. In conclusion, EO and OA blends significantly improved the broiler chickens' performance, inflammatory, and immune response and reduced intestinal lesions. A marked difference occurred in favor of combined than single treatments compared to antibiotic treatment facing the C. perfringens' infection.