Despite that in-feed antibiotics (IFA) are still in use in a number of countries, during the last decade an important number of in vivo studies on alternatives to IFA have been conducted for the weaned period. This in vivo work complemented with in vitro work, carried out with intestinal porcine epithelial cells (IPEC-J2), provide a siginificant amount of knowledge that allow understand the underlying mechanisms of action of the different IFA alternatives. The main innate immune response addressed has been the Toll-like receptors (TLR)-dependent, nuclear factor enhancing kappa light chains of activated B cells (NF-κB) canonical signaling pathway. Gene expression of pro-inflammatory (interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor (TNF)-α) and regulatory (IL-10, transforming growth factor (TGF)-β) cytokines, and sometimes their concentrations in intestinal tissues or in blood serum or plasma, as well as systemic markers (e.g., haptoglobin, C-reactive protein (CRP), calprotectin) have been investigated as outcome variables of inflammation. An important gut function, permeability which is particularly affected during weaning has been addressed directly ex vivo using Ussing chambers, in vitro with cell lines (e.g., Caco2 cells), but most often indirectly using molecular biology techniques for gene expression (and sometimes protein relative concentrations) of key tight junction (TJ) proteins. Literature analysis reveals that, taken collectively these data are rather convincing and promising. They also provide a better understanding of the modes of action of IFA alternatives especially on intestinal, and sometimes systemic inflammation. Many functional nutrients including L-amino acids and derivatives (e.g., arginine, N-acetylcysteine, glutamine, glycine, serine), plant components (e.g., terrestrial and marine polysaccharides, polyphenolic compounds) and essential oils have indeed anti-inflammatory properties when given to piglets at optimal concentrations and durations of treatment. This holds true for many probiotic microorganisms (bacteria, yeasts) that have been carefully evaluated in terms of strains, dosage and dietary or nutritional context. In a few cases, mixtures of such categories of substances (e.g., bioactive nutrients, feed components, probiotics) have been evaluated. The mixtures could be protective as the individual substances alone, but sometimes synergistic or antagonistic effects have been disclosed. This encourages to pursue studies of interactions among IFA. One potential limitation of many published works is that they are often based only on gene expression approaches, with few studies associating physiological or functional variables (e.g., epithelial permeability). Future work aimed at controlling gut permeability and inflammation in young pigs should continue to propose novel solutions that are sustainable, environment-friendly, economically viable to the producer and acceptable to the consummer.