Medwakh smoking has radically expanded among the youth in the Middle East and around the world. The rising popularity of medwakh/dokha usage is linked to the onset of several chronic illnesses including cardiovascular diseases and cancers. The present study aims to elucidate changes in the salivary proteome of medwakh smokers and explore the resultant pathological alterations in comparison to non-smokers. Statistical measurements reveal significant alterations in the abundance of 74 protein profiles in medwakh smokers compared to non-smokers. Medwakh smoking affected proteins with roles in cell anchorage and adhesion (FERMT3, CAPZA2, ACTN1, TLN1), immune responses, and inflammation (CFI, PSME2, S100A12, CHI3L1, HRG, RNASE2, ORM2), oxidative and anti-oxidative stress responses (NCF4, ERP 29, AKRA1, NADPH, NCF1B) and various cell metabolic processes (G6PD, HEXB, HK3, EEF1A1, PYGL, UGP2, EEF1A1). In our investigation, several novel proteins such as CFI, RNASE2, ORM2, NQO2, SULT1A1, TSN, and UBA1 were also discovered. These proteins play key roles in the initiation of various pathologies and are unique in medwakh smokers. The high significant increase in the abundance of involucrin suggests an alarming squamous cell differentiation in medwakh smokers. In addition, various pathways related to mitochondrial damage, oxidative burst, cell adhesion, migration, differentiation, and proliferation were significantly altered in medwakh smokers. The knowledge gained would help to elucidate the adverse effects of medwakh smoking, especially among adolescents, raising awareness of plausible health hazards, thereby improving the quality of life.