Gastric cancer (GC) is a neoplasia with an increase in incidence and mortality over the next years. Currently, the treatment of this malignancy consists of surgery in association with the administration of platinum compounds or 5-FU capecitabine. The identification of novel biomarkers related to the GC progression is a key point in re-modulating the pharmacological treatment to get a more efficient patient response. In this study, we reported that Hormonally Upregulated Neu tumor-associated Kinase (HUNK) promotes gastric cancer progression by regulating cell homeostasis. Particularly, we demonstrated that HUNK is responsible for the increase in gastric cancer cell proliferation through the binding and phosphorylation of p38 MAP kinase and that its depletion is associated with a reduction of survival both in gastric cancer cells and patient-derived organoids. Further, we reported that HUNK regulates positively the expression of MUC16/CA-125, a well-known cancer prognostic marker. Our findings shed light, for the first time, on the molecular mechanisms regulated by HUNK in gastric cancer cells making this kinase a promising candidate for novel targeted therapeutic strategies.