Drug resistance (DR) is one of the challenges in treating retinoblastoma (Rb) that warrants novel approaches. With the emerging evidence on the role of small extracellular vesicles (sEVs) as a drug-delivery carrier system, in this study, we derived the drug-resistant (DR) clones of Y79 cells and evaluated the efficacy of sEVs-loaded with carboplatin (sEVs-CPT) to reverse the chemoresistance. Drug-resistant clones of Y79 cells (DR-Y79) were systematically developed through sequential exposure to carboplatin (CPT), showcasing a sixfold increase in inhibitory concentration when compared to parental Y79 cells (IC₅₀: 41.4 µg/mL and 6.2 µg/mL) (P<0.0001). These DR-Y79 cells show higher expression of ABCG2 and higher expression of DR genes than parental Y79 cells (P<0.0001). The sEVs were isolated from the conditioned media of Y79 cells using ultracentrifugation (UC) and characterized. Further, the sEVs were loaded with CPT and achieved higher encapsulation efficiency at one hour, and drug release of sEVs-CPT was highest at ∼80% at pH 5.0. The cytotoxicity of sEVs-CPT on Y79 cells and DR-Y79 was higher when compared to the CPT (IC50: 3.5 µg/mL vs 6.2 µg/mL; 23.1 µg/mL vs 41.2 µg/mL) (p<0.0001). This study demonstrates that sequential exposure to CPT generates DR clones of Y79 cells, which could serve as an appropriate model to evaluate the efficacy of drugs. The sEVs-CPT were highly effective in enhancing cytotoxicity in DR-Y79 cells, and appear to hold promise as a novel complimentary drug delivery system.