Colibacillosis, which is the leading cause of infectious diseases resulting in mortality and economic losses in poultry is triggered by Avian pathogenic Escherichia coli (APEC). Conventionally, antibiotic growth promoters (AGP) are incorporated into poultry diets to control infectious diseases and boost performance. However, because of the problem of antimicrobial resistance, synthetic antibiotics are now restricted or banned in animal production in some countries. In this study, we carried out a challenge experiment by inoculating healthy broilers with APEC (106 cfu/mL) by oral gavage on day 21 of the experiment and orally administering various treatments five days post challenge for five days; synthetic antibiotics (T2), Vernonia amygdalina (bitter leaf) extracts (T3), no treatment (T4), which were compared with the control that wasn’t challenged (T1). The experiment lasted for 42 days. Performance, hematological and histological studies were carried out. The results show that the challenged birds became diseased with the development of visible lesions, which ameliorated over time to varying extents with the use of synthetic antibiotics and Vernonia treatments. Overall, the performance of the birds with the use of Vernonia (T3) was comparable with that of synthetic antibiotics (T2) without eliciting any adverse hematological effects on the broilers. We therefore conclude that Vernonia can be safely used as a supplement for disease prevention in broiler chicken production