Avian pathogenic Escherichia coli (APEC) poses significant health risks in poultry, leading to infections that impact productivity. APEC strains exhibit antibiotic resistance, complicating treatment options. Current vaccination strategies are limited in their protective scope, necessitating the exploration of innovative alternatives such as probiotics, bacteriophages, immune stimulants, and antimicrobial peptides (AMPs). AMPs show promise due to their rapid action against resistant bacteria and minimal resistance development. Additionally, small molecules have demonstrated effectiveness against various APEC serotypes, supporting the development of new antimicrobial therapies. Overall, a multifaceted approach addressing APEC’s virulence factors and incorporating novel therapies is crucial for controlling colibacillosis in poultry and mitigating risks to human health.