This study aimed to assess the impact of an oral formulation combining bromelain (250 mg) derived from (L.) Merr. Jambs and diosmin mcgSMIN Plus (250 mg) on visual acuity and central retinal thickness (CRT) in patients undergoing anti-VEGF intravitreal maintenance therapy (IVT) for cystoid, center-involving diabetic macular edema (DME). A total of forty patients with type 2 diabetes and center-involving DME, all receiving anti-VEGF maintenance therapy, were prospectively enrolled in a case-control study. Group A (20 eyes) was administered one tablet containing 250 mg of bromelain and 250 mg of diosmin mcgSMIN Plus twice daily for a period of two months. Group B (20 eyes) was monitored without drug administration until the next IVT. After two months and IVT administration, the groups were switched. At the end of the study, the collected data were divided into two groups. The treatment group included data from patients who received the dietary supplement, and the control group consisted of data from patients who were only observed during anti-VEGF therapy. Best-corrected visual acuity (BCVA) and CRT measurements were assessed at baseline, after two months, and after four months. A statistically significant improvement in CRT was observed in the treatment group compared to the control group during follow-up ( < 0.05). However, the improvement in BCVA was not statistically significant. Orally administered combination of bromelain 250 mg and 250 mg diosmin mcgSMIN Plus has positive impact on central retinal thickness in patients treated for cystoid center-involving diabetic macular edema (DME) with anti-VEGF intravitreal maintenance therapy.