Objective The aim of this study was to investigate macular perfusion changes and ganglion cell complex (GCC) loss in patients with unexplained visual loss following vitrectomy and silicone oil (SO) tamponade, and to evaluate the correlation between retinal blood flow and GCC loss using optical coherence tomography angiography (OCTA) and optical coherence tomography (OCT). Methods This retrospective study included seven eyes (seven patients) with unexpected visual loss after vitrectomy and SO tamponade. OCTA was used to evaluate the alterations in retinal vessel density (VD) in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and radial peripapillary capillary plexus (RPCP). OCT was used to measure the thickness of GCC and retinal nerve fiber layer (RNFL). Medical records of patients were reviewed. Results Quantitative analysis of OCTA images revealed a significant reduction in SCP VD in the affected eyes compared with the controls (all sections P < 0.05). No difference was found in GCC thickness, but FLV (focal loss volume) and GLV (global loss volume) were significantly higher in the affected eyes (both P < 0.001). SCP VD was inversely correlated with FLV and GLV. Conclusions Silicone oil-related severe visual loss was associated with superficial retinal microvasculature damage and ganglion cell apoptosis.