Purpose <p>To evaluate the effects of topical 0.3% nepafenac on choroidal thickness (CT), and the choroidal vascularity index (CVI) in diabetic and non-diabetic patients following uncomplicated phacoemulsification.</p> Methods <p>This prospective, randomized study included 104 eyes of 104 patients undergoing uneventful cataract surgery. Participants were randomized to receive topical nepafenac (Group 1, <i>n</i> = 54) or no nepafenac (Group 2, <i>n</i> = 50) and were further stratified by diabetic status (Groups 1A, 1B, 2A, 2B). Optical coherence tomography (OCT) and Enhanced Depth Imaging-OCT assessments of central macular thickness (CMT), CT, and CVI were conducted preoperatively, at postoperative week 1, and week 6. Nepafenac was administered once daily for 6 weeks in Group 1. Intergroup and intragroup changes were analyzed using appropriate statistical tests.</p> Results <p>At postoperative week 6, CVI was significantly lower in the nepafenac group compared with controls (<i>p</i> = 0.015), while CMT and CT showed no significant between-group differences. In diabetic participants, CVI increases at week 1 and week 6 were significantly attenuated with nepafenac treatment (<i>p</i> = 0.015 and <i>p</i> = 0.021, respectively). Non-diabetic participants demonstrated no significant nepafenac-related changes in CMT, CT, or CVI (<i>p</i> &gt; 0.05). CT increased during early postoperative follow-up in all groups, whereas no participant developed diabetic macular edema.</p> Conclusions <p>Topical nepafenac significantly reduces postoperative increases in CVI—particularly in diabetic patients—suggesting a protective effect against inflammation-associated choroidal vascular alterations. Nepafenac may help preserve choroidal vascular integrity after cataract surgery, highlighting its value as an adjunctive anti-inflammatory therapy, especially for diabetic individuals at higher inflammatory risk.</p>