Urothelial carcinoma (UC) is one of the most common malignancies with complex pathogenesis, tumor recurrence, and metastasis. Recent multiplex expensive molecular assays can accurately identify the diagnostic genetic aberrations in urine cytology; however, they lack worldwide availability and are of high cost. To date, cystoscopy, an invasive procedure, remains the gold standard for diagnosis. Receptor for Advanced Glycation End Products (RAGE) and TP53 mutations are involved in carcinogenesis and invasiveness of many human cancers. Hence, this study aims to develop simpler reliable molecular and non-invasive UC identification and follow-up tools in Egyptian patients harboring these aberrations. Patients and methods: The study enrolled 200 patients with urinary symptoms. Urines and bladder biopsies were obtained from all participants. High-Grade Urothelial Carcinoma cells (HGUC) were diagnosed in urine cytology according to the Paris system for reporting urine cytology. TP53 mutations were assessed in urine cytology using Polymerase Chain Reaction (PCR) followed by bidirectional Sanger sequencing. The expression of RAGE in UC biopsies was evaluated by immunohistochemistry (IHC). Recurrence and lymph node metastasis follow-up data were collected and Meta-analysis was performed. Results: Positive HGUC in urine significantly showed mutations in TP53 exons 2+3, 4, and 5 representing 36%, 64%, and 74% respectively with significant concordance with higher tumor grade, stage, recurrence, and lymph nodes metastasis, which parallelly, exhibited higher RAGE IHC expression in biopsies compared to cystitis. Conclusions: TP53 mutations assessment in urine cytology is promising as a simple molecular non-invasive tool for screening and follow-up UC patients. In the same context, RAGE IHC expression in UC biopsies could be suggested as a potential novel pathological screening for molecular-targeted UC therapies and follow-up