This study aimed to evaluate the role and efficacy of vitrectomy in the management of chronic diabetic macular edema (DME) refractory to intravitreal anti-vascular endothelial growth factor (anti-VEGF) and corticosteroid treatments. A systematic review and meta-analysis were performed by searching the Embase, Medline, and gray literature. Eight hundred and thirty-nine studies were retrieved and eight were selected (three for quantitative synthesis and five for qualitative synthesis). Visual acuity (VA) and central macular thickness (CMT) were compared between the vitrectomy-treated and control groups (treated with anti-VEGF and intravitreal corticosteroid injection) using the standardized mean difference (SMD) with 95% confidence intervals (CIs) and P-values. There was no significant difference in post-operative VA between the vitrectomy-treated and control groups (SMD = −0.31, 95% CI: −0.76, 0.14, P = 0.18). However, CMT was significantly lower in the vitrectomy group than in the control group (SMD = −0.31, 95% CI: −0.76, 0.14, P = 0.18). In addition, the incidence of postoperative complications was higher in the control groups than that in the vitrectomy group.This systematic review and meta-analysis suggest that vitrectomy may be viable for the management of chronic DME refractory to anti-VEGF and corticosteroid agents. Although there was no significant difference in VA, the CMT was significantly reduced in the vitrectomy group. Moreover, the incidence of post-operative complications was lower in the vitrectomy group than that in the control group. Further studies are needed to confirm these findings and identify patient subgroups that may benefit from vitrectomy.