Vancomycin (VAN), a cationic glycopeptide antibiotic, represents a last-resort therapeutic remedy for life-threatening infections caused by multidrug resistant Gram-positive pathogens. However, biliary excretion of intravenously administered VAN in the gastrointestinal (GI) tract results in the VAN-resistant Enterococcus faecium emergence, a major cause of hospital-acquired infections. Instead of developing new antibiotics, we hypothesize that breaking the connection between intravenous antibiotic use and GI antimicrobial resistance may protect current antibiotics. Here, we develop a novel anti-VAN material via hybridizing hairy cellulose nanocrystals with a Food and Drug Administration (FDA)-approved resin to remove the excess antibiotic from the GI tract before it impacts bacteria and selects for resistance. In vitro studies show that VAN removal is regulated by electrostatic interactions via a time-dependent diffusion-controlled process that is not significantly influenced by the physiological pH, ionic strength, or the components of simulated intestinal fluid. Aligned with the in vitro findings, the oral administration of anti-VAN adjuvant effectively sequesters VAN in the murine GI tract and prevents the VAN resistance enrichment following the VAN treatment of E. faecium colonized mice. The anti-VAN adjunctive therapy may protect intravenous VAN, which is a step forward in addressing the global threat of antimicrobial resistance.