Natural oligomeric procyanidin (OPC) with high biological and pharmacological activities was successfully used to synthesize OPC-insulin (OPC-INS) nanoparticles with different aggregation sizes for sustained and controlled delivery of hydrophilic insulin. The aggregation size of OPC-INS nanoparticles was regulated by OPC concentration, pH value, and incubation time. The fabrication mechanism would be that OPC and insulin self-assembled into a mixture of insulin aggregates via intermolecular interactions. In the self-assembly of insulin, OPC could serve both in the encompassing of insulin aggregates as a stabilizer and cross-linking different amounts of insulin aggregates into OPC-INS nanoparticles as interphase. OPC-INS nanoparticles not only demonstrated effective insulin drug loading but also exhibited aggregation-size-dependent and controlled insulin release performance in vitro. In the best case for OPC-INS nanoparticles, only ∼21% of insulin was released in 37 days. This study showed that the OPC-INS nanosystem is promising to serve as a long-acting insulin release formulation, and OPC has great potential as a drug carrier for nanomedicine.