The accurate diagnosis and treatment of oral squamous cell carcinoma (OSCC) requires an understanding of its genomic alterations. Liquid biopsies, especially cell-free DNA (cfDNA) analysis, are a minimally invasive technique used for genomic profiling. We conducted comprehensive whole-exome sequencing (WES) of 50 paired OSCC cell-free plasma with whole blood samples using multiple mutation calling pipelines and filtering criteria. Integrative Genomics Viewer (IGV) was used to validate somatic mutations. Mutation burden and mutant genes were correlated to clinico-pathological parameters. The plasma mutation burden of cfDNA was significantly associated with clinical staging and distant metastasis status. The genesTTN,PLEC,SYNE1, andUSH2Awere most frequently mutated in OSCC, and known driver genes, includingKMT2D,LRP1B,TRRAP,andFLNA, were also significantly and frequently mutated. Additionally, the novel mutated genesCCDC168,HMCN2, STARD9, andCRAMP1were significantly and frequently present in patients with OSCC. The mutated genes most frequently found in patients with metastatic OSCC wereRORC,SLC49A3, andNUMBL.Further analysis revealed that branched-chain amino acid (BCAA) catabolism, extracellular matrix–receptor interaction, and the hypoxia-related pathway were associated with OSCC prognosis. Choline metabolism in cancer, O-glycan biosynthesis, and protein processing in the endoplasmic reticulum pathway were associated with distant metastatic status. About 20% of tumors carried at least one aberrant event in BCAA catabolism signaling that could possibly be targeted by an approved therapeutic agent. We identified molecular-level OSCC that were correlated with etiology and prognosis while defining the landscape of major altered events of the OSCC plasma genome. These findings will be useful in the design of clinical trials for targeted therapies and the stratification of patients with OSCC according to therapeutic efficacy.