Bladder cancer (BCa) is one of the most prevalent cancers worldwide and accounts for high morbidity and mortality. This study intended to elucidate potential key biomarkers related to the occurrence, development, and prognosis of BCa through an integrated bioinformatics analysis. In this context, a systematic meta-analysis, integrating 18 microarray gene expression datasets from the GEO repository into a merged meta-dataset, identified 815 robust differentially expressed genes (DEGs). The key hub genes resulted from DEG-based protein–protein interaction and weighted gene co-expression network analyses were screened for their differential expression in urine and blood plasma samples of BCa patients. Subsequently, they were tested for their prognostic value, and a three-gene signature model, including COL3A1, FOXM1, and PLK4, was built. In addition, they were tested for their predictive value regarding muscle-invasive BCa patients’ response to neoadjuvant chemotherapy. A six-gene signature model, including ANXA5, CD44, NCAM1, SPP1, CDCA8, and KIF14, was developed. In conclusion, this study identified nine key biomarker genes, namely ANXA5, CDT1, COL3A1, SPP1, VEGFA, CDCA8, HJURP, TOP2A, and COL6A1, which were differentially expressed in urine or blood of BCa patients, held a prognostic or predictive value, and were immunohistochemically validated. These biomarkers may be of significance as prognostic and therapeutic targets for BCa.
