Experimental and clinical studies confirm that the progressive deterioration of visual acuity in diabetic retinopathy (DR) results from apoptosis of retinal neuronal structures and fibrovascular proliferation in the fundus. This study aimed to assess the extent of retinal apoptosis in experimental DR and evaluate the effects of cellular protein kinases blockade. Experimental DR was induced in male Wistar rats via streptozotocin administration (50 mg/kg; “Sigma- Aldrich”, China). Group 1 (control) received no treatment for hyperglycemia. Group 2 received insulin (“Actrapid HM Penfill”, Denmark) at 30 U every other day. Group 3 was treated with the protein kinase inhibitor sorafenib (“Cipla”, India) at 50 mg/kg. Group 4 received both insulin (as in Group 2) and sorafenib (as in Group 3). Caspase-3 and Bax protein levels in retinal lysates were analyzed by immunoblotting, and caspase-3 expression was also assessed immunohistochemically (“ThermoFisher Scientific”, USA). During DR progression, the levels of precursor and active forms of proapoptotic proteins caspase-3 and Bax increased in parallel. Sorafenib alone did not affect hyperglycemia- induced retinal apoptosis, whereas insulin, either alone or in combination with sorafenib, significantly reduced both proapoptotic markers, indicating suppression of DR-associated apoptosis. The immunohistochemical study results confirmed elevated caspase-3 expression in ganglion cells, as well as in the processes and bodies of astrocytes and Müller cells, reflecting reactive gliosis typical of DR. The reduction of apoptosis with insulin treatment, alone or combined with sorafenib, suggests that insulin may counteract sorafenib's potential proapoptotic effects, while preserving sorafenib's ability to prevent DR-related morphological changes.