Platelet activation and thrombus propagation are driven in part by reactive oxygen species generated by NADPH oxidase, together with cytoplasmic calcium (Ca²⁺) mobilization and cyclic adenosine monophosphate (cAMP) signaling. Natural-product extracts with antiplatelet activity are attracting growing pharmacological interest as adjuncts or alternatives to conventional antiplatelet drugs, whose clinical use is limited by bleeding risk and, in some patients, drug resistance. This study investigated the effects of aqueous and methanol extracts of  Carica papaya leaves (CPL) on platelet NADPH oxidase activity, cytoplasmic Ca²⁺ mobilization, and cAMP production in vitro, with the aim of characterizing the mechanistic basis of their antiplatelet activity. Methods: Platelet-rich plasma or washed platelets were incubated with CPL aqueous or methanol extract before stimulation with adenosine diphosphate (ADP) or collagen. Ca²⁺ mobilization was measured by flow cytometry using Fluo-3-AM, cAMP was measured with a luminescence-based cAMP-Glo assay, and NADPH oxidase activity was measured with a NADP/NADPH-Glo assay. Both extracts suppressed collagen- and ADP-induced intracellular Ca²⁺ mobilization relative to control, although the methanol extract did not inhibit Ca²⁺ mobilization induced by the higher collagen concentration (30.0 µg/mL). The aqueous extract increased cAMP production induced by ADP by 118.5% - 146.1% of control, whereas the methanol extract suppressed cAMP levels at all ADP concentrations tested. Both extracts inhibited ADP-induced NADPH oxidase activity, with suppression ranging from 26.9% - 77.5% for the aqueous extract and 51.6 - 80.7% for the methanol extract across ADP concentrations of 3.0 - 100 µM. CPL extracts inhibit platelet NADPH oxidase activity and Ca²⁺ mobilization, and differentially modulate cAMP production, supporting their potential as natural antiplatelet agents that act through multiple, partly convergent signaling pathways rather than a single molecular target.