The papaya (Carica papaya) leaf (PL) contains high levels of saponins and polyphenolic compounds, and historically, it has been used as a folk medicine for numerous ailments, including cancer. PL is traditionally prepared by hot water extraction; however, optimised extraction conditions have not been assessed. This study optimised conditions for the extraction of saponins from PL and assessed their antioxidant capacity and antipancreatic cancer activity. Optimisation was achieved using response surface methodology. Saponins and total phenolic compounds were assessed for their antioxidant, free radical scavenging, ion-reducing capacity, and antipancreatic cancer activity. Optimal aqueous extraction conditions were 85 °C, 25 min. and a water-to-leaf ratio of 20:1 mL g−1. Ethanol extracts demonstrated higher antioxidant, free radical scavenging and ion-reducing capacity, as well as antipancreatic cancer activity. This study revealed that the PL contains numerous bioactive compounds, with significant anticancer activity warranting further studies on the isolation and characterisation of individual bioactive compounds from the PL.