Stress granules (SGs), which are phase-separating organelles that serve as protective cellular mechanisms in response to various harmful stimuli, have an unclear role in oxaliplatin resistance. Here, we establish a causal link between SG formation and oxaliplatin resistance in GC. Notably, we identify a key SG nucleator, namely, ubiquitin-associated protein 2-like (UBAP2L), as a previously unrecognized critical factor in mediating oxaliplatin resistance. UBAP2L-nucleated SG-mediated inhibition of apoptosis is associated with the recruitment of receptor of activated protein C kinase 1 (RACK1), a known promoter of apoptosis, to these entities. Transcriptional upregulation of UBAP2L is enhanced by oxaliplatin-induced phosphorylation and activation of heat shock factor protein 1 (HSF1) via AKT. Inhibiting either SG or HSF1 significantly overcomes oxaliplatin resistance in vivo. These findings demonstrate that UBAP2L-nucleated SGs play a vital role in mediating oxaliplatin resistance, with elevated SG levels emerging as a promising therapeutic target for overcoming this resistance.