Several lytic bacteriophages effective at destroying a genetically diverse population of Clostridium perfringens were isolated from the environment, extensively characterized, and used to formulate a multivalent bacteriophage cocktail designated “INT-401.” Two in vivo studies were conducted to determine the cocktail's efficacy in controlling necrotic enteritis (NE) caused by C. perfringens. The first study investigated the efficacy of INT-401 and a bacteriophage-derived, toxoid-type vaccine in controlling NE in C. perfringens–challenged broiler chickens. The study was designed as a proof-of-concept battery cage study with birds reared until 28 days old. Compared with the mortality observed with the C. perfringens–challenged but untreated chickens, oral administration of INT-401 significantly (P < 0.05) reduced the mortality of the C. perfringens–challenged birds by 92%. Overall, INT-401 was more effective than the toxoid vaccine in controlling active C. perfringens infection. The second study was conducted to investigate the effectiveness of the cocktail when administered via oral gavage, feed, or drinking water. The study was conducted in floor pens, with birds reared to 42 days old. INT-401 administered by all three methods significantly (P < 0.05) reduced mortality. Weight gain and feed conversion ratios were significantly better in the C. perfringens–challenged chickens treated with INT-401 than in the C. perfringens–challenged, phage-untreated control birds. The data indicate that delivering INT-401 to broiler chickens via their drinking water or feed may be an effective means for controlling NE caused by C. perfringens and may improve weight gain and feed conversion ratios in birds with clinical or subclinical NE.