Introduction Oral cancer accounts for 3% of all malignancies diagnosed worldwide annually. Midkine (MK) plays a role in oncogenesis and tumor progression, including cell migration, mitogenesis, antiapoptosis, and angiogenesis. Aim and Objective To study and compare MK expression in various grades of oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Methodology This is a cross-sectional study where 60 archival specimens of OSCC, OED, and control were taken for immunohistochemical examination. Antibody MK (A-9) SC-46701 mouse monoclonal (200µg/mL, Santacruze Biotechnology) was used for immunohistochemical staining. The stained sections were observed under the objective (100 ×) of research microscope (DM 1000 LED) with computer-assisted image analyzer (Leica Application Suit V-4.1). Quantitative analysis was done to count MK reactive cells in all groups. Statistical analysis was performed using Kruskal–Wallis H test with posthoc Bonferroni's test for multiple group comparisons, and p-value < 0.05 was considered as statistically significant. Results MK expression was observed in OSCC and OED and was absent in control. The distribution of average percentage positivity was significantly higher in OED compared with OSCC and control. Statistically significant correlation was found between the size of the tumor and increased MK expression. Conclusion MK protein is overexpressed in OED and OSCC, and can be used as biological marker for early detection.