Landfill leachate, a complex mixture of different solid waste compounds, is widely known to possess toxic properties. However, the fundamental molecular mechanisms engaged with landfill leachate exposure inducing cellular and sub-cellular ramifications are not well explicated. Therefore, we aim to examine the potential of leachate to impair mitochondrial machinery and its associated mechanisms in human peripheral blood lymphocytes. On assessment, the significant increase in the dichlorofluorescein (DCF) fluorescence, accumulation of 8-Oxo-2′-deoxyguanosine (8-oxo-dG), and levels of nuclear factor erythroid 2–related factor 2 (Nrf-2) strongly indicated the ability of the leachate to induce a pro-oxidant state inside the cell. The decrease in the mitochondrial membrane potential and alterations in the mitochondrial genome observed in leachate-exposed cells further suggested the disturbances in mitochondrial machinery. Moreover, these mitochondrial-associated redox imbalances were accompanied by the increased level of NF-κβ, pro-inflammatory cytokines, and DNA damage. In addition, the higher DNA fragmentation, release of nucleosomes, levels of polyadenosine diphosphate ADP-ribose polymerase (PARP), and activity of caspase-3 suggested the involvement of mitochondrial mediated apoptosis in leachate exposed cells. These observations were accompanied by the low proliferative index of the exposed cells. Conclusively, our results clearly indicate the ability of landfill leachate to disturb mitochondrial redox homeostasis, which might be a probable source for the immunotoxic consequences leading to plausible patho-physiological conditions in humans susceptible to such environmental exposures.