Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with limited therapeutic options and poor prognosis, underscoring the urgent need for novel molecular targets. Here, we identify phosphoserine phosphatase (PSPH) as a key oncogenic driver in ESCC. This study systematically investigated the oncogenic functions of PSPH in ESCC progression and the associated molecular mechanisms. Functional studies revealed that PSPH overexpression markedly enhanced ESCC cell proliferation, migration, and invasion in vitro, while PSPH knockdown exerted opposing effects. Mechanistically, transcriptomic and phosphoproteomic analyses identified the mitogen-activated protein kinase (MAPK) pathway as the key downstream effector of PSPH. In vivo xenograft studies corroborated these findings, demonstrating that PSPH overexpression markedly promoted tumor growth. Notably, the pharmacological inhibitor of c-Jun N-terminal kinase (JNK) effectively abrogated PSPH-induced tumor progression, unequivocally establishing the MAPK pathway as the dominant mediator of PSPH oncogenic functions. Our findings establish PSPH as a key driver of ESCC progression, promoting migration, proliferation, and invasion via MAPK signaling activation. These results position PSPH as a promising therapeutic target for improving outcomes in patients with ESCC.