Protease activity has been associated with pathological processes that can lead to cancer development and progression. However, understanding the pathological unbalance in proteolysis is challenging since changes can occur simultaneously at protease, their inhibitor and substrate levels. Here, we present a pipeline that combines peptidomics, proteomics and peptidase predictions for studying proteolytic events in saliva associated with oral squamous cell carcinoma (OSCC) prognosis and lymph node metastasis. Our results suggest that cleavage products differentially abundant in the saliva of patients with (N+) or without (N0) nodal metastasis exhibit potential of prognostic value in oral cancer whereas reduced levels of peptidase inhibitors disturb the proteolytic balance in saliva of OSCC patients with worse prognosis.