Administration of prescribed therapeutic antimicrobials for prophylactic purpose is still widely practiced in global swine production to maintain gut health and growth of weanling pigs. Three studies were conducted to comprehensively understand the impact of prescribed therapeutic antimicrobials (mg/kg), including chlortetracycline (220), tiamulin (31.2) and ZnO (2358), on the digestive utilization of dietary fiber, starch and crude fat, endogenous alkaline phosphatase (AP) activity and expression, bacterial species level of the gut microbiome changes and their interrelationships and contributions to growth promotion and gut health in weanling pigs. In Study-1, antimicrobials improved (P<0.05) weanling pig growth performance. The growth-promoting effect of antimicrobials were associated (P<0.05) with increased feed intake and reduced digestive utilization of dietary fiber rather than the unaffected (P>0.05) digestive utilization of starch and crude fat. The full-length 16S rRNA gene sequencing data showed that antimicrobials substantially reduced or eliminated (P<0.05) the cecal digesta and fecal relative abundances of specific bacterial species within Lactobacillus, Streptococcus and zoonotic Campylobacter. Fecal relative abundances of p-1088-a5 sp., Parasutterella sp., Defluviitaleaceae sp., Selenomonas sp., Mitsuokella sp., Lachnoclostridium sp. and Streptococcus orisratti displayed (P<0.05) the potential to serve as non-invasive biomarkers for the prediction of growth performance. In Study-2, antimicrobials up-regulated (P<0.05) the AP maximal enzyme activity (i.e., Vmax) in the gut and plasma. Plasma AP Vmax showed a positive linear correlation (P<0.05) with feed intake and growth rate, suggesting it as a novel biomarker for predicting porcine growth performance. Antimicrobials also demonstrated an improvement (P<0.05) in the gut health of weanling pigs, as indicated by a lower fecal score. Furthermore, antimicrobials increased (P<0.05) the cecal digesta and fecal relative abundances of bacterial endocellulase gene GH5-p4818Cel5_2A. Fecal relative abundances of GH5-p4818Cel5_2A, Blautia obeum, Oribacterium sp., Lactobacillus salivarius, p-2534-18B5 sp., dgA-11 sp., Mucispirillum sp. and Streptococcus orisratti exhibited a linear correlation (P<0.05) with gut health, suggesting their potential roles as biomarkers for predicting porcine gut health. In Study-3, antimicrobials down-regulated (P<0.05) the permeability and inflammation-related gene mRNA abundances in the hindgut which were associated (P<0.05) with growth performance and gut health endpoints as well as abundances of the identified specific bacterial species in weanling pigs.