Phosphoserine phosphatase (PSPH), a key enzyme in the L-serine synthesis pathway, has been found to promote cancer progression through autophagy modulation. Here, we explored the functional role and molecular mechanisms of PSPH in colorectal cancer (CRC). PSPH expression in CRC was evaluated using bioinformatics analysis, RT-qPCR, and Western blot. Functional assays including colony formation, transwell migration/invasion, and flow cytometry were performed. Molecular mechanisms were investigated using Western blot analysis of autophagy-, proliferation-, apoptosis-associated proteins and AMPK-ULK1 signaling components. The biological significance of PSPH was validated using xenograft models and tumor immune microenvironment analysis. We found that PSPH expression was elevated in CRC patients and correlated with poor prognosis. PSPH overexpression promoted CRC cell proliferation, migration, and invasion while suppressing apoptosis and PSPH knockdown produced opposite effects. PSPH overexpression activated AMPK-ULK1 signaling to induce protective autophagy in CRC cells. These oncogenic effects were abrogated by AMPK/ULK1 depletion or chloroquine-mediated autophagy inhibition. In vivo, PSPH overexpression accelerated CRC tumor growth and promoted tumor immune evasion by upregulating PD-L1 expression and reducing CD8+ T cell infiltration. Overall, our findings establish PSPH as a critical oncoprotein that drives CRC progression through AMPK-ULK1-mediated autophagy activation and immune evasion.