Toxic metals from industrialization and urbanization pose major human health risks, and mixture-based exposure requires broader toxicity assessment. This study investigated the effects of a mixture of arsenic, lead, mercury, cadmium, chromium (VI), and nickel on pancreatic function in rats (45 male/45 female; n = 5 per group), focusing on sex- and duration-specific differences after 28 and 90 days of exposure. The metals were administered as a single mixture dissolved in deionised water via oral gavage. Evaluated parameters included pancreatic metal levels, histopathology, serum glucose, amylase, malate dehydrogenase 1 (MDH-1) activity, redox status, and bioelements. Dose levels were based on human exposure data to reflect realistic scenarios. Metals accumulated in pancreatic tissue, causing dose- and time-dependent histopathological changes, including acinar cell vacuolization, vascular congestion, and Langerhans islet alterations. Males showed more pronounced vascular and islet changes, while females had greater acinar alterations. In males, higher doses decreased glucose and amylase and increased MDH-1 activity, while females showed more variable responses. Males demonstrated adaptive responses to oxidative stress over time, while females experienced more persistent stress. These findings reveal sex-, dose-, and duration-dependent effects of toxic metal(oid) mixtures on pancreatic function, indicating that individually safe doses may be harmful when combined.