SET Domain Bifurcated histone lysine methyltransferase 1 (SETDB1), a histone H3K9 methyltransferase, is frequently overexpressed in multiple malignancies, including gastric cancer (GC). However, its molecular functions and regulatory mechanisms in GC progression remain poorly defined. Here, we identified the role of SETDB1 in gastric cancer using molecular and cell biology methods, combining RNA-seq and RNC-mRNA seq. Here, we found SETDB1 was markedly upregulated in gastric cancer tissues compared with adjacent non‑tumor tissues. Functional analyses revealed that SETDB1 knockdown suppressed GC cell proliferation and migration, whereas overexpression had the opposite effect. Notably, SETDB1 promoted cell proliferation independently of its methyltransferase activity, while its enhancement of migration required enzymatic function. Mechanistically, SETDB1 activated the unfolded protein response (UPR) to stimulate c-MYC transcription and cell-cycle progression, and engaged the mTOR–4EBP1 axis to promote HIF1α translation. These findings reveal a dual regulatory role for SETDB1 in GC and identify it as a promising therapeutic target for managing gastric cancer.