Oral squamous cell carcinoma (OSCC) is one of the most common epithelial malignancies of multifactorial etiology linked with considerable mortality and morbidity. Generally, OSCC arises from pre-existing oral lesions quoted as oral potentially malignant disorders. Early diagnosis of OSCC is an attractive strategy to increase the survival rate of patients. Despite the accessibility of prominent diagnostic tools, many factors restrain the successful application of these approaches. The discovery of novel alternative methods to diagnose cancer definitively with higher selectivity and sensitivity has aroused scientific interest. Metabolomics is an unbiased analytical approach for qualitative and quantitative analyses of different metabolites in cells, tissues, or biological fluids and their alterations in response to pathophysiological stimuli. Several coupled techniques, together with chromatographic platforms, have facilitated metabolic profiling and, at the same time, detected cancer biomarkers, which are crucial for an effective treatment process. This overview discusses some of the most recent technological advances in metabolomics and focuses on their application to reveal the underlying causes of OSCC and their potential implications for personalised medicine.