Objective <p>Bladder cancer poses a significant clinical challenge due to its high recurrence and heterogeneity, necessitating novel biomarkers. To explore the multidimensional role of TM4SF19, a tetraspanin family member, as a potential diagnostic and prognostic biomarker in bladder cancer (BLCA) through multi-omics analysis.</p> Methods <p>This study integrated multi-omics data from public databases (TCGA, GEPIA, cBioPortal, TIMER, LinkedOmics) to analyze TM4SF19 expression, genomic alterations, prognostic significance, immune infiltration associations, and drug sensitivity in bladder cancer. Analytical methods included differential expression analysis (limma package), survival analysis (Kaplan-Meier and Cox regression), nomogram construction, functional enrichment (GSEA, KEGG), immune microenvironment assessment (MCPcounter, TIMER), and drug sensitivity evaluation (GDSC database). Statistical analyses were performed using R software (v4.0.2) with significance set at <i>p</i> &lt; 0.05</p> Results <p>TM4SF19 was significantly upregulated in bladder cancer tissues (<i>p </i>&lt; 0.01) and demonstrated high diagnostic accuracy (AUC = 0.831). High TM4SF19 expression correlated with advanced pathological stage, lymphovascular invasion, and poorer overall survival (<i>p </i>&lt; 0.05). Functional analysis linked TM4SF19 to PI3K-Akt/MAPK signaling pathways and immune modulation, showing negative correlations with CD8⁺ T cells and B cell infiltration. TM4SF19 expression also negatively correlated with sensitivity to Trametinib and Docetaxel but positively with Navitoclax and AR-42, indicating its role in chemotherapy resistance.</p> Conclusion <p>TM4SF19 is a promising diagnostic and independent prognostic biomarker in BLCA, influencing tumor progression through signaling pathways and immune microenvironment modulation. Its association with chemotherapy resistance highlights its potential as a therapeutic target.</p>