D-penicillamine (DPA) is an amino-thiol that has been established as a copper chelating agent for the treatment of Wilson's disease. DPA reacts with metals to form complexes and/or chelates. Here, we investigated the survival rate extension capacity and modulatory role of DPA on Cu2+-induced toxicity in Drosophila melanogaster. Adult Wild type (Harwich strain) flies were exposed to Cu2+ (1 mM) and/or DPA (50 μM) in the diet for 7 days. Additionally, flies were exposed to acute Cu2+ (10 mM) for 24 h, followed by DPA (50 μM) treatment for 4 days. Thereafter, the antioxidant status [total thiol (T-SH) and glutathione (GSH) levels and glutathione S-transferase and catalase activities] as well as hydrogen peroxide (H2O2) level and acetylcholinesterase activity were evaluated. The results showed that DPA treatment prolongs the survival rate of D. melanogaster by protecting against Cu2+-induced lethality. Further, DPA restored Cu2+-induced depletion of T-SH level compared to the control (P < 0.05). DPA also protected against Cu2+ (1 mM)-induced inhibition of catalase activity. In addition, DPA ameliorated Cu2+-induced elevation of acetylcholinesterase activity in the flies. The study may therefore have health implications in neurodegenerative diseases involving oxidative stress such as Alzheimer's disease.