Dengue virus (DENV) is one of the most prevalent arboviruses worldwide, and the lack of specific antiviral treatments highlights the need to develop new therapeutic strategies based on natural compounds. This study evaluated the antiviral potential of Carica papaya leaf extracts against DENV replication in cell culture, considering the presence of bioactive metabolites previously reported in the literature, including flavonoids, alkaloids, terpenoids, and phenolic compounds. Extracts were obtained through maceration and ultrasound-assisted extraction using different solvent systems. The extraction yields varied significantly depending on the solvent employed, with the hexane extract showing the highest recovery, while methanol and ethanol also allowed an efficient extraction of bioactive fractions. Cytotoxicity assays in BHK-21 cells after 24, 48, and 72 hours of incubation revealed mean cytotoxic concentrations ≥1 mg/mL for all extracts, indicating low toxicity in cell culture. Antiviral assays performed through viral plaque quantification demonstrated that all extracts inhibited DENV replication, with the hexane extracts exhibiting the lowest mean inhibitory concentration values, indicating a stronger antiviral effect at lower concentrations. Overall, these findings suggest that Carica papaya leaf extracts, particularly those obtained with nonpolar solvents, contain metabolites with promising antiviral properties that have not been previously described in the literature, as most studies have focused on extracts obtained with polar solvents. The identification and characterization of these compounds represent an essential step toward the development of plant-derived antiviral agents targeting dengue virus.