Diabetes mellitus can induce release of free radicals and oxidative stress, which can trigger production of cytokines. Vernonia amygdalina has antidiabetic activity due to its phytochemical constituents. This work was designed to determine possible immunological alterations in the plasma levels of TNF-α and Interleukin-10 (IL-10) in the traditional application of V. amygdalina (Ewuro) leaves in the treatment of diabetes mellitus. The study populations include all 33 diabetes mellitus patients (51-67 years; male, 21; female, 12) who had not commenced any form of medication or treatment and received herbal treatment in 10 herbal homes of Saki West, a local government area in Nigeria. Twenty-seven agematched volunteers who were treated on insulin medication in the hospital almost within the same period were also investigated. Patients who were positive to acid-fast bacilli sputum test, Plasmodium spp., identification, HBsAg, anti-HCV, and HIV-1 p24 assays were not included. Plasma TNF-α, IL-10, HBsAg, anti-HCV, and HIV-1 p24 were determined in the patients by ELISA while identification of acid-fast bacilli and Plasmodium spp. were carried out by Ziehl-Neelsen and Giemsa thick blood-film staining, respectively. There was a significant decrease in the plasma levels of TNF-α, IL-10, and glucose in diabetes mellitus patients after the administration of raw liquid extract of V. amygdalina and insulin compared to their basal samples before the commencement of the treatment (p < 0.05). The work revealed a significant increase in plasma TNF-α, IL-10, and glucose in diabetes patients, which returned to normal plasma values after treatment using raw liquid extract of V. amygdalina leaves and insulin.