Updated project metadata. COVID-19 is the most impacting global pandemic of all times with over 600 million infected and 6.5 million deaths worldwide, in addition to an unprecedented economic impact. Despite the many advances in scientific knowledge about the disease, much remains to be clarified about the molecular alterations induced by SARS-COV-2 infection. For this reason, it is urgent to carry out studies that help to clarify the molecular changes after SARS-COV-2 infection. In this work, we show a hybrid proteomics and in silico interactomics strategy to establish a COVID-19 salivary protein profile. The differential proteome was narrowed down by PLS-DA tool and the enrichment analysis was performed with FunRich. In parallel OralInt was used to determine interspecies PPIs between humans and SARS-CoV-2. Five dysregulated biological processes were identified in COVID-19 proteome profile: Apoptosis, Energy Pathways, Immune Response, Protein Metabolism and Transport. Interactomics analysis allowed the identification of new PPIs between the virus and the host, representing molecular aspects that could be important to understand this disease.