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Simple Summary: Mitochondrial dysfunction and respiratory function changes have been associated with the initiation and progression of cancer. However, no study has comprehensively investigated the relationship between these mitochondrial-related factors and prognosis in a large number of patients with oral squamous cell carcinoma (OSCC). Here, we retrospectively investigated the expression of mitochondrial tumor-suppressor and DNA-repair proteins (PGC-1α, TFAM, OGG1, MTUS1, and SIRT3) in patients with OSCC and evaluated the relationship between their expression and prognosis. The expression levels of the five proteins were associated with patient outcomes. The 3-year disease-specific survival (DSS) rates of patients showing positive expression of all selected proteins were significantly higher than those of patients showing a lack of expression. Particularly, based on the results of multivariate analysis, negative expression of PGC-1α is related to a poor prognosis of OSCC. Low PGC-1α expression and vascular invasion may be clinically effective predictors of oral cancer prognosis. Mitochondrial dysfunction and respiratory function changes have been consistently associated with the initiation and progression of cancer. The purpose of this study was to retrospectively investigate the expression of mitochondrial tumor-suppressor and DNA-repair proteins in patients with oral squamous cell carcinoma (OSCC) and to evaluate the relationship between their expression and prognosis. We enrolled 197 patients with OSCC who underwent surgical resection between August 2013 and October 2018. Clinical, pathological, and epidemiological data were retrospectively collected from hospital records. The expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), mitochondrial transcription factor A, mitochondrial tumor suppressor gene 1, silent information regulator 3, and 8-hydroxyguanine DNA glycosylase was investigated using immunochemistry. The 3-year disease-specific survival (DSS) rates of patients showing positive expression of all selected proteins were significantly higher than those of patients showing a lack of expression. Multivariate analysis revealed that the expression of PGC-1α (hazard ratio, 4.684) and vascular invasion (hazard ratio, 5.690) can predict the DSS rate (p < 0.001). Low PGC-1α expression and vascular invasion are potential clinically effective predictors of the prognosis of OSCC. [ABSTRACT FROM AUTHOR]