Zika virus (ZIKV) remains a major global health concern, and no specific antiviral therapy is currently available. Amazonian natural bioactive compounds are promising candidates, but their therapeutic use is often limited by poor solubility and stability. We investigated the antiviral and immunomodulatory potential of Piper alatipetiolatum essential oil and zerumbone encapsulated in PEG–PCL nanoparticles (NPs) against ZIKV. Molecular docking was performed against the ZIKV NS5 methyltransferase to explore potential target engagement by the tested compounds. Antiviral activity was evaluated at key infection stages (adsorption, replication, and viral inactivation) using plaque-forming unit assays in Vero cells. Immunomodulatory effects were assessed by profiling cytokines in supernatants from nanocomposite-treated peripheral blood mononuclear cells (PBMCs) using high-sensitivity ELISA and ProQuantum assays. Docking analyses indicated that ishwarol B, a major constituent of Piper essential oil (along with 6-ishwaron and ishwarane), had the highest predicted affinity for the NS5 methyltransferase. Zerumbone-loaded nanoparticles (Z-PEG-PCL) showed the strongest stage-dependent anti-ZIKV activity, achieving 100% reduction during replication and inactivation and 60% during adsorption, whereas Piper essential oil-loaded nanoparticles (P-PEG-PCL) showed moderate effects (40% adsorption, 45% replication, and 58% inactivation). Z-PEG-PCL exhibited dose-dependent modulation, suppressing IL-6 and IL-8 at low concentrations while upregulating IL-8 at higher doses. Conversely, P-PEG-PCL consistently induced IL-6 but reduced IL-8 and IP-10. Although both systems attenuated TNF-α, they exerted antithetical effects on MCP-1, highlighting distinct mechanistic pathways for each nanoformulation. Overall, PEG–PCL nanoencapsulation enabled the delivery of Amazonian bioactives with combined antiviral and immunomodulatory effects, supporting this platform as a promising strategy for ZIKV-targeted interventions.