PurposeObesity and its associated metabolic disorders, such as T2DM and MeS, are a growing public health problem worldwide. Our goal was the identification of protein patterns that are uniquely characteristic of higher BMI, MeS, and T2DM in a Brazilian population.Experimental DesignSaliva and plasma proteomes, clinical parameters were analyzed in a population from the state of Rio de Janeiro, Brazil, a mixed‐race population. Volunteers were sorted by their BMI into normal (n = 29), overweight (n = 25), and obese (n = 15) and were compared with individuals with MeS (n = 23) and T2DM (n = 11).ResultsThe Random Forest (RF) predictive model revealed that three clinical variables, BMI, HOMA‐IR, and fasting blood glucose, are most important for predicting MeS and T2DM. A total of six plasmatic proteins (ABCD4, LDB1, PDZ, podoplanin, lipirin‐alpha‐3, and WRS) and six salivary proteins (hemoglobin subunit beta, POTEE, T cell receptor alpha variable 9–2, lactotransferrin, cystatin‐S, carbonic anhydrase 6), are enhanced in T2DM and in MeS.Conclusions and Clinical RelevanceOur data revealed similar alterations in protein composition across individuals with abnormal weight gain, T2DM, and MeS. This finding confirms the close link between these conditions at the molecular level in the studied population, potentially enhancing our understanding of these diseases and paving the way for the development of novel diagnostic tools.