Mechanistically, esketamine potentiated 5-FU-driven AMP-activated protein kinase (AMPK) phosphorylation, leading to inhibition of both mammalian target of rapamycin (mTOR) and hyaluronan-mediated motility receptor (HMMR).<h4>Conclusion</h4>Esketamine enhances 5-FU chemosensitivity in colorectal adenocarcinoma by activating the AMPK/mTOR/HMMR signaling axis, thereby suppressing tumor progression and metastatic potential. Here, HMMR is linked to colorectal adenocarcinoma.