Administration of antibiotics as feed additives in broilers resulted in prompting of some undesirable effects such as the rising emergence of multi-drug resistant (MDR) bacteria, so scrutinizing for new alternatives like herbs is the up to date task for global health. This study was designed to determine the in-vitro antibacterial and ex-vivo immunomodulatory efficacy of garlic (Allium sativum) and ginger (Zingiber officinale) extracts post dietary supplementation for 900-one-day-old Sasso broiler chicks. The in-vivo protective actions of these extracts against avian pathogenic MDR Escherichia coli (E. coli) O78 challenge was evaluated after 21 days of extracts supplementation. Garlic extract exhibited broader antimicrobial spectra against MDR E. coli O78 and S. aureus isolates. Through the 21 days of garlic or ginger dietary supplementation, the chicks’ innate immune response was modulated via various mechanisms including phagocytosis augmentation, bactericidal activity enhancement and nitric oxide (NO) production reduction, together with triggering the IL-1β, IL-6 and IFN-γ cytokines expression levels in comparison with the non-supplemented chicks. It is tempting to speculate that protection against pathogenic E. coli O78 challenge was high in chicks supplemented with each individual extract with severe reduction in the bacterial colony forming units in chicks’ vital organs that confirm the extracts immunomodulatory activity and provide a mechanism(s) of their protective actions. Our data suggest promising useful insights to garlic and ginger dietary supplementation in broilers that may be safe for consumers from antibiotic toxic metabolites’ residues and protective against the risk of infection with bacterial pathogens