A serious infection in avian species can be caused by Clostridium perfringens (C. perfringens). Because of the harmful consequences that antibiotics have on public health, reducing their usage in the animal industry is a major global concern. As an alternative to antibiotics, nanoparticles (NPs) have been used more and more recently to target bacteria. Zinc oxide (ZnO), one of these NPs, exhibited antibacterial activity even at low concentrations. Consequently, at 14 days, 75-day-old Cobb broiler chicks were separated into 5 equal groups (15 birds each divided into triplicate, 5 bird per replicate). The groups were calssified as G1, G2, G3, G4 & G5. G1 was infected with C. perfringens type A; G2 was infected & given zinc oxide nanoparticles (ZONPs); G3 was infected with C. perfringens & given doxycycline as an antibiotic; G4 received ZONPs continuously for 35 days; & G5 was the negative control. For two successive days, 4×108 colony forming units (CFU) of C. perfringens type A/mL/bird were given orally to birds in infected groups. ZONPs in the treatment groups received a total dose of 150 µg/bird. Bird performance is measured for 35 days, & data is gathered on body weight (BW), feed conversion (FC), feed conversion rate (FCR), clinical signs score, & mortalities. Moreover, immune organ indices & the microbial loads in the caecum & intestine were assessed. Remarkably, BW improvements (P < 0.05) were noted in ZONPs treated group & ZONPs / C. perfringens infected group, in contrast to those in G1. Compared to G1, treatment with ZONPs lowered the colonization of C. perfringens in the caeca & intestine, lessened the severity of clinical symptoms, & decreased mortality. Thymus, bursa, & spleen relative weights varied considerably (P < 0.05) between treatment groups. When ZONPs were administered alone or in conjunction with infection, the spleen’s relative weight was considerably (P < 0.05) larger in treated birds than in control & antibiotic-treated birds. In conclusion, ZONPs positively affect the BW & FCR, improve the relative weight of immune organs, & can decrease the C. perfringens count in the intestine, positively impacting performance, general health, & gut health integrity. However, ZONPs also reduce the population of gut microbes. On the other hand, birds that received antibiotic treatment showed adverse effects on a few metrics. Therefore, more investigation into the use of ZONPs in broiler diets and their safety for the health of humans and avian species is still advised.