Background: Oral cancer is the 17th most common cancer worldwide, with a mortality rate of 1.8%. Their incidence varies considerably, with a clear prevalence in South Asian countries. In Africa, the mortality rate for cancers of the oral cavity is 1.3%. Senegal is a perfect illustration a perfect illustration of the seriousness and scale of this disease, with 177 new cases recorded in 2020, for a mortality rate of 1.4%. To add to the knowledge of the molecular mechanisms involved in the carcinogenesis of these pathologies in Senegal, mutations in the C-MYC proto-oncogene were examined in 22 patients with oral cavity cancers and compared with samples from 32 control individuals. Methods: Cancerous tissue (CT) and adjacent normal tissue (ANT) were sampled from diseased individuals, whereas whole blood was obtained from control individuals (C). A total of 67 samples were collected: 32 from controls, 22 from CTs, and 13 from ANTs of diseased individuals. Total DNA was extracted and polymerase chain reaction (PCR) amplification of exon 2 of the C-MYC gene was performed, followed by Sanger sequencing. Mutation analysis was performed using Mutation Surveyor Software v5.0.1. The effect of each non-synonymous mutation on the function of the encoded protein was determined using the POLYPHEN-2, PANTHER-PSEP, and PROVEAN algorithms. The probability of non-synonymous mutations causing diseases was predicted using Prediction of human Deleterious Single Nucleotide Polymorphism (PhD-SNP) and Predicting disease associated variations using GO terms (SNP&GO). The impact of non-synonymous variations on the stability of the encoded protein was determined using I-Mutant2 and In-silico analysis of Protein Stability (INPS). Results: Of the study participants, 63% were females. The mean age of patients was 46.43 \pm 13 years, with extremes of 14 and 83 years and the age range of 40–70 years as the most representative age group. Only 5% of patients were alcohol drinkers and 15% were smokers. Most patients (80%) had stage III or IV tumors with lymph node invasion. A low polymorphism rate in exon 2 of the C-MYC proto-oncogene was identified, with one synonymous substitution (Q48Q) found in a diseased individual (CT and ANT). The non-synonymous substitutions (D31N, D31E, V33G, Y36N, and Y36D) found in the controls were predicted to be damaging and pathogenic, and might decrease the stability of the encoded protein. Conclusions: Our results indicate that the C-MYC protooncogene is not involved in the occurrence and progression of oral cavity cancers in Senegalese patients. However, the mutations found in controls could provide new markers for the early clinical diagnosis of oral cancer.