Objectives The present study evaluated the predictive value of staging and grading parameters concerning the presence of lymph-node metastases, overall survival (OS), and relapse-free survival (RFS) of patients with oral squamous cell carcinoma (OSCC). Materials and methods HE-stains of 135 surgically treated (R0) primary OSCCs were analyzed using a both microscopic and software-based approach. Depth of invasion (DOI) and resection margins (RM) were measured, and each case was graded according to the malignancy grading system as described by Anneroth et al. and Bryne et al. on two different sites of the tumor (surface and invasion front; TS and IF). Results Parameters that could be identified as significant predictors of OS and RFS were UICC cancer stage (p = 0.009 andp = 0.012); pT-stage as defined in the 7th edition (p = 0.029 and 0.015) and, after restaging using DOI, 8th edition (p = 0.023 andp = 0.005) of the TNM classification of malignant tumors; the presence of lymphonodular metastases (LM) (p = 0.004 andp = 0.011); degree of keratinization (p = 0.029 andp = 0.042); and pattern of growth (p = 0.029 andp = 0.024) at the TS after applying a binary scale for both parameters. Also, when directly comparing the most extreme subgroups (scores 1 and 4) of lymphoplasmacytic infiltration at the IF, there was a significant difference in OS (p = 0.046) and RFS (p = 0.005). Invasion of blood vessels (p = 0.013) and perineural invasion (p = 0.023) were significantly associated with a lower OS. Age lower than 60 years (univariatep = 0.029, multivariatep = 0.031), infiltration of lymphatic vessels (p = 0.003), infiltration of nerves (p = 0.010), pT-stage (8th edition) (p = 0.014), degree of keratinization at the IF (p = 0.033), and nuclear polymorphism at the IF (p = 0.043) after conversion to a binary scale were found to be significant prognostic parameters regarding the presence of LM. DOI evolved as a significant predictor for OS (p = 0.006), RFS (p = 0.003), and LM (p = 0.032) in metric and grouped analysis. Conclusions The current evaluation revealed depth of invasion as strongest histologic predictor of metastatic tumor growth, overall survival, and relapse-free survival in OSCC, confirming the current adaption of the T-classification. Other distinct histologic grading parameters investigated during this study can give valuable indications of a tumor's potential aggressiveness, but the exact site, mode, and procedure need further exploration.