Background <p>Necrotic enteritis is a devastating economic disease caused by <i>Clostridium perfringens</i> in poultry. NetB toxin from <i>C. perfringens</i> type G is the major responsible cause of necrotic enteritis. After the ban on growth-promoting antibiotics, alternative effective intervention approaches such as the vaccination of birds were considered critical to control necrotic enteritis. To date, no commercial vaccines with proven efficacy have been approved against necrotic enteritis. In this study, we evaluated the efficacy of the oral and parenteral vaccines based on NetB antigen from <i>C. perfringens</i> to choose the best prime-boosting vaccination strategy against necrotic enteritis. The broiler chickens were orally vaccinated with either previously developed recombinant probiotic bacterium, <i>Lactobacillus casei</i> strain expressing NetB toxoid, followed by a parenteral booster by the purified recombinant NetB toxoid (oral/parenteral), or the recombinant NetB toxoid alone (parenteral-only).</p> Results <p>Immunizations of birds with these vaccines elicited strong specific anti-NetB antibody responses and provided significant protection against the infectious challenge. Additionally, the vaccinated birds represented significant mean body weight gains compared with birds in control groups during the experiment.</p> Conclusions <p>The current study showed that oral and parenteral vaccines using NetB antigen from <i>C. perfringens</i> could provide significant protection against necrotic enteritis in broiler chickens.</p>