Purpose To assess the functional and anatomical outcomes of intravitreal dexamethasone implant Ozurdex® in eyes with diabetic macular edema that did not adequately respond to vascular endothelial growth factor inhibitors. Methods Multicenter, retrospective, and real-life case series study conducted on consecutive diabetic macular edema patients who underwent treatment with one or more dexamethasone implant injections and were followed up for a minimum of 12 months. Subjects were divided into three groups: I—naïve patients, II—previously treated eyes that received three intravitreal antivascular endothelial growth factor inhibitors injections before the study (early switch), and III—previously treated eyes that received >3 intravitreal antivascular endothelial growth factor inhibitors injections before the study (late switch). Primary endpoints were best-corrected visual acuity and central retinal thickness at month 12. Results A total of 129 eyes (21 naïve and 108 previously treated, Group II: 32 and Group III: 76) were included. At month 12, best-corrected visual acuity significantly improved from 0.27 ± 0.23 and 0.31 ± 0.22 at baseline to 0.36 ± 0.25 and 0.37 ± 0.23 at month 12 in naïve and previously treated eyes, respectively, and p = 0.0063 and 0.0060, respectively. Central retinal thickness, in naïve and previously treated eyes, was significantly reduced from 483.0 ± 143.4 and 431.3 ± 115.5 µm, at baseline, to 278.8 ± 72.1 and 269.3 ± 66.2 µm, at month 12, respectively, and p < 0.0001 each, respectively. Best-corrected visual acuity improvement was significantly greater in both absolute and percentage values, p = 0.0393 and 0.0118, respectively, in Group II than in Group III. Conclusion In eyes with insufficient response to antivascular endothelial growth factor inhibitors, switching to dexamethasone at the time to 3-monthly antivascular endothelial growth factor inhibitors injections provided better functional outcomes than those that received >3 antivascular endothelial growth factor inhibitors injections.