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SEMA5B plays an important role in the maintenance of neural development and is highly environment dependent in tumorigenesis. The roles of SEMA5B in prostate cancer remain underexplored. This study investigates SEMA5B's functions in prostate cancer, revealing its role as a tumor suppressor transcriptionally regulated by androgen receptor and uncovering novel biomarkers and potential immunotherapeutic mechanisms. We analyzed SEMA5B's expression in cancer and its spatial association with cells in the tumor microenvironment using single-cell transcriptome sequencing datasets and spatial transcriptome sequencing samples. Using bulk RNA-seq data, we analyzed the immune infiltration of SEMA5B in prostate cancer. The association of SEMA5B with androgen receptor signaling and with metabolic pathways was evaluated by transcriptome and enrichment analysis. The phenotypes, cell cycle, apoptosis, and mitochondrial metabolic function of prostate cancer cell lines were further evaluated. SEMA5B regulation by androgen receptor was examined by gene knockdown, androgen/enzalutamide treatment, and epigenomics. Finally, the effect of SEMA5B on prostate cancer in vivo was detected by tumor xenograft model. Pan-cancer single-cell analysis revealed that SEMA5B's expression showed significant tumor type specificity and spatially correlated with immune cell infiltration. SEMA5B is associated with abundant lymphocyte and immune-inflammatory microenvironment in prostate cancer. SEMA5B overexpression inhibited tumor cell proliferation, migration, and invasion. Moreover, high SEMA5B is associated with oxidative phosphorylation and low glycolytic profile. SEMA5B expression is positively correlated with androgen receptor. Androgen receptor inhibition and androgen stimulation affected the expression of SEMA5B. ChIP confirmed the binding of androgen receptor to the SEMA5B promoter. Finally, SEMA5B was verified to induce cell cycle arrest and apoptosis and reduce tumor growth. SEMA5B inhibits tumor malignant phenotype and is associated with immune-inflammatory tumor microenvironment. SEMA5B can regulate mitochondrial oxidative metabolism and induce cell cycle arrest and cell apoptosis, inhibiting the growth of prostate cancer.