Chikungunya virus (CHIKV), a re-emerging arbovirus of the Alphavirus genus, causes acute febrile illness often followed by persistent polyarthritis or arthralgia. Due to its rapid transmission and the absence of approved antivirals or licensed vaccines, there is an urgent need for effective therapeutic strategies. Among potential antiviral targets, the nonstructural proteins nsP2 (a helicase/protease) and nsP4 (an RNA-dependent RNA polymerase) are essential for viral replication. In this study, we evaluated five compounds based on the isatin scaffold: one parent isatin molecule and four synthetic derivatives (ID11–ID14) functionalized with semicarbazone or thiosemicarbazone groups. Cytotoxicity assays confirmed low toxicity for all compounds, with CC₅₀ values above 500 µM. Using a CHIKV replicon model in BHK-CHIKV-NCT cells, compounds ID13 and ID14 significantly reduced EGFP fluorescence, indicating strong inhibition of viral replication. Infectious particle assays supported these results, with all compounds displaying dose-dependent antiviral effects and EC₅₀ values between 20 and 33.6 µM. No significant reduction in viral entry was observed in entry inhibition assays, suggesting that the compounds act post-entry by targeting replication. Molecular docking simulations revealed a predicted propensity of all compounds to interact with important residues of nsP2 and nsP4. Notably, compound ID14 showed the strongest predicted affinity for both enzymes, while compound ID13 demonstrated the highest antiviral efficacy in vitro. These findings highlight isatin derivatives as promising candidates for CHIKV antiviral development and support further exploration of dual-target strategies focusing on viral replication proteins.