Combatting antimicrobial-resistant bacteria is a high priority for both public health and agriculture in the United States and globally. Antibiotic use in animals and humans is considered a major risk factor in the development of antibiotic-resistant bacteria in animals, humans, and the environment. A worldwide emphasis on research into the development of new alternatives to antibiotics is ongoing. Alternatives to antibiotics are broadly defined as any substance that can be substituted for therapeutic drugs, which are increasingly becoming ineffective against pathogenic bacteria, viruses, or parasites. One promising approach involves host-directed immunomodulatory therapies, whereby natural mechanisms in the host are exploited to enhance therapeutic benefit. The objective is to initiate or enhance protective antimicrobial immunity while limiting inflammation-induced tissue injury. The interaction between poultry nutrition, nutrients, and dietary factors and the bird’s immune response has long been known. However, the interplay between nutritional processes and the immune system is incompletely understood. Specifically, precise cellular and molecular immune responses invoked by feed components and the role of the gut barrier and microbiota on the interaction between the immune system and nutrition remains to be fully elucidated. Further, this review will point out some of the areas that have been either neglected when studying the effects of nutrition and nutrients on immune function (the effect of the gut microbiome) or the non-intentional effects of over-feeding various nutrients on the avian immune response (feed-induced inflammation and meta-inflammation).