Infectious bursal disease (IBD) is an acute immunosuppressive disease of chickens that, despite various vaccination strategies, continues to cause significant economic losses in the poultry industry. The current study sought to determine the prevalence of IBDV infection in relation to various vaccination programs and other risk factors in three different Egyptian Governorates. As a result, 69 chicken flocks were studied clinically and molecularly, with 62 flocks (case flocks) suspected of being naturally infected with the infectious bursal disease virus (IBDV) and 7 flocks (control flocks) apparently healthy. The investigated diseased flocks had whitish diarrhea, depression, ruffled feathers, bursal lesions, nephrosis, nephritis, hemorrhages on muscles, and petechial hemorrhages at the junction of the proventriculus and gizzard. The mortality rate ranged from 0.31 to 25%. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), IBDV was detected in 47 of 62 (75.8%) of the tested flocks, while no IBDV was found in the control flocks. The highest prevalence rates were found in chickens aged 18–20 days old and of the Sasso, Indian River, and Hubbard breeds. The detection rate was 100% in chicken flocks vaccinated with Intermediate vaccine (Nobilis Gumboro D78), Intermediate+ Intermediate plus, Vaxxitek-ND-IBD, and Innovax-ND-IBD. Remarkably, the most effective vaccine program was in flocks that used the Vaxxitek-ND –IBD+ Intermediate vaccine (33.3%). It could be concluded that single-dose IBDV vaccines provide insufficient protection against IBDV strains, particularly live ones, due to maternal antibody interference. Meanwhile, vaccination with a recombinant vaccine followed by one or two booster doses of live vaccines provides good protection and prevents IBDV infection. Therefore, it is necessary to utilize the outcome of the field application best trials to update and improve the IBDV immunization programs with keeping in mind the biosecurity practices in chicken farms as well as the complete gene sequencing to detect mutations and virus evolution.