The tumor microenvironment plays a pivotal role in cancer initiation, progression, invasion, metastasis, and therapeutic response. Among its various components, the tumor–stroma ratio (TSR) has emerged as a simple yet clinically valuable histopathological biomarker with significant prognostic implications across multiple solid malignancies. TSR quantifies the relative proportion of tumor cells and surrounding stromal tissue within histological sections. Numerous studies have demonstrated that tumors with abundant stromal components are frequently associated with aggressive biological behavior, advanced disease stage, increased metastatic potential, and poorer survival outcomes. Traditionally assessed by visual microscopic estimation, TSR evaluation has recently evolved through digital pathology and quantitative image analysis, improving objectivity and reproducibility. This review summarizes the biological basis of the tumor microenvironment, methodologies for quantitative TSR assessment, current clinical applications, prognostic significance in different cancers, advantages and limitations of digital image analysis, and future perspectives involving artificial intelligence and computational pathology. Current evidence supports TSR as an inexpensive, reproducible, and promising prognostic biomarker that may complement conventional histopathological parameters in personalized cancer management.