Background Oral squamous cell carcinoma (SCC) is a significant health burden, particularly in developing countries. Cyclin D1 and p53 regulate cell cycle progression and apoptosis, while tumor-associated tissue eosinophilia (TATE) influences the tumor microenvironment. In this study, we aimed to assess the correlation between cyclin D1, p53, and TATE expression and tumor grade and histological subtypes in oral SCC. Methodology A total of 90 SCC patients were studied at the Pakistan Institute of Medical Sciences Hospital over one year. Tumors were categorized into well-differentiated, moderately differentiated, poorly differentiated, and non-keratinizing subtypes. Immunohistochemical staining for cyclin D1 and p53 was graded (0-3), while TATE was classified as grade 1 (0-10), grade 2 (11-20), and grade 3 (>20 eosinophils per high-power field). Statistical analyses were performed using SPSS version 21 (IBM Corp., Armonk, NY, USA). Results Cyclin D1 and p53 expression significantly increased with tumor grade (p = 0.001), whereas TATE was more prevalent in lower-grade SCC (p = 0.03). Non-keratinizing SCC showed the highest cyclin D1 (66.6%) and p53 (100%) expression, whereas 66% had grade 3 TATE. Conclusions Cyclin D1 and p53 are potential prognostic markers for SCC, whereas TATE may influence tumor differentiation.