This work compared the antibacterial activity and in vivo effects of nitazoxanide and tylosin against infected broilers with antibiotic resistant Clostridium perfringens field strain to control necrotic enteritis disease. Both in vitro and in vivo assessment studies were used. Firstly, C. perfringens was isolated with a total rate of 46% from liver and intestine samples of diseased broilers. By using PCR molecular typing all tested isolates were type A (produced only alpha-toxin (cpa virulence gene)) and included Bla and tetK (resistant genes). Using antibiotic sensitivity test they showed multi-drugs resistance against amoxiclave, tetracycline, gentamicin, clindamycin, sulphamethoxazole-trimethoprim and cefoxitin. Minimal inhibitory and bactericidal concentrations (μg/ml) were 0.4 and 12 for nitazoxanide and 0.7 and 49 for tylosin respectively. Then, a total of 90 one-day-old-chicks were divided into 6 groups; G1: negative-control, G2: infected-control, G3: non-infected (nitazoxanide 15.4 mg/kg body weight), G4: non-infected (tylosin 20 mg/kg body weight), G5: infected-nitazoxanide (15.4 mg/kg), and G6: infected-tylosin (20 mg/kg). Treatments lasted for 5 days in drinking water. No adverse effects on liver or kidney parameters were recorded in non-infected treated groups. Both treatments overcome the infection signs, C. perfringens count and revealed a significant improvement in most of inflammatory and biochemical parameters to their normal levels especially, G5 reflected a significant increase in total protein, albumin, globulin while reduced alanine and aspartate aminotransferase and gamma-glutamyl transferase activities, C-reactive protein, uric acid, and creatinine levels than G2. Finally, nitazoxanide revealed a significant anti-clostridial activity as tylosin for the control of necrotic enteritis in broilers.