The spread of bacterial resistance to antimicrobials (AMA) have intensified efforts to discontinue the non-therapeutic use of AMA in animal production. Finding alternatives to AMA, however, is currently encumbered by the obscure mechanism that underlies their growth-promoting action. In this report, we demonstrate that combinations of antibiotics and zinc oxide at doses commonly used for stimulating growth or preventing post-weaning enteritis in pigs converge in promoting microbial production of bile acids (BA) in the intestine. This leads to tissue-specific modifications in the proportion of BA, thereby amplifying BA signaling in intestine, liver, and white adipose tissue (WAT). Activation of BA-regulated pathways ultimately reinforces the intestinal protection against bacterial infection and pathological secretion of fluids and electrolytes, attenuates inflammation in colon and WAT, alters protein and lipid metabolism in liver, and increases the circulating levels of the hormone FGF19. Conceivably, these alterations could spare nutrients for growth and improve the metabolic efficiency of AMA-treated animals. This work provides evidence that BA act as signaling molecules that mediate host physiological, metabolic, and immune responses to the AMA-induced alterations in gut microbial metabolism, eventually permitting the growth-promoting action of AMA. Consequently, BA emerge as a promising target for developing efficacious alternatives to AMA.