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This study was conducted to determine for the first time the immunological, histopathological, histochemical, and ultrastructural changes; hematological and biochemical alterations; and poikilocytosis induced in Clarias gariepinus by Voliam flexi® 40% WG (thiamethoxam + chlorantraniliprole). Beside control fish, juvenile C. gariepinus were subjected to three sublethal concentrations of Voliam flexi® (43.5, 87.5, and 175 mg/L) for 15 days. Voliam flexi® induced immunotoxic impairments in C. gariepinus, such as a decrease in some immunity variables (lysozyme and phagocyte activity, immunoglobulin concentration, and nitro blue tetrazolium level). It also caused an extreme increase in the levels of primary cytokines (interleukin-1β and IL-6), compared with the control. The toxic effects of Voliam flexi® increased gradually with the increasing concentrations tested. Histological examination of the liver demonstrated necrosis, vacuolated hepatocytes (fatty deposition), melanomacrophage centers, foci of inflammatory cells, congested and dilated blood sinusoids, hepatic degeneration, fibrosis increment (Sirius Red stain), and glycogen depletion, as well as cytopathological alterations. We conclude that the toxic effects of Voliam flexi® must be restricted or prevented by using control mechanisms in aquatic systems., (Copyright © 2022 Elsevier Ltd. All rights reserved.)