Our previous study demonstrated that moderate inhibition of intestinal autophagy was beneficial to alleviate early weaning stress in piglets, but the detailed mechanism behind this was unclear. Microbiota-mediated enterocyte autophagy helps maintain intestinal homeostasis. This study investigated the effects of inhibition or activation of autophagy in intestinal microbial community compositions and metabolite profiles in piglets. Eighteen 24-day-old weaned piglets were divided into three groups (each treatment of six piglets) and treated daily with rapamycin (RAPA), chloroquine (CQ) or a control volume of normal saline (CON group). Before the formal trial, the piglets were allowed to acclimatize for 3 days, and then the trial period was 14 days. Collected samples from the ileum and colon underwent 16S rRNA gene sequencing and metabolite analysis. Significant differences in microbial composition were observed in both the ileum and colon of the RAPA and CQ groups compared to the CON group ( < 0.05). In addition, the relative levels of abundance of , , , and in the ileum and , , , , , , , and in the colon were improved in piglets fed the RAPA diet, whereas the relative levels of abundance of , and in the ileum and and in the colon were enhanced in the CQ group ( < 0.05). Meanwhile, metabolomic analysis showed that there were significant differences in metabolites among all groups ( < 0.05), and KEGG enrichment analysis revealed that differential metabolites were mainly enriched in the ABC transporters and biosynthesis of amino acids pathways. Furthermore, these metabolites were closely related to differential microorganisms ( < 0.05). Overall, autophagy inhibition regulates the composition of intestinal microorganisms and their metabolites, and these differential metabolites are significantly correlated with differential intestinal microorganisms, which may in turn affect the production performance of weaned piglets.