The efficacy of intravitreal anti-VEGF may be reduced in vitrectomized eyes due to accelerated drug clearance. Given its longer durability, brolucizumab may represent a suitable therapeutic option. However, its efficacy in vitrectomized eyes remains to be explored. Herein, we describe the management of a macular neovascularization (MNV) in a vitrectomized eye with brolucizumab after unsuccessful treatment with other anti-VEGF. A 68-year-old male was treated with pars plana vitrectomy for epiretinal membrane in his left eye (LE) in 2018. After surgery, best corrected visual acuity (BCVA) improved to 20/20 with a remarkable reduction of metamorphopsia. After 3 years, the patient returned, presenting visual loss in the LE due to MNV. He was treated with intravitreal bevacizumab injections. However, after the loading phase, an increased lesion size and exudation with worsening BCVA were detected. Therefore, the treatment was switched to aflibercept. However, after three monthly intravitreal injections, further worsening was recorded. Treatment was then switched to brolucizumab. Anatomical and functional improvement was noticed 1 month after the first brolucizumab injection. Two additional injections were performed, and further improvement was recorded with BCVA recovery to 20/20. At the last follow-up visit 2 months after the third injection, no recurrence was detected. In conclusion, determining whether anti-VEGF injections are efficacious for vitrectomized eyes would be helpful for ophthalmologists managing such patients, as well as when considering pars plana vitrectomy in eyes at risk of MNV. In our case, brolucizumab was found to be effective after unsuccessful treatment with other anti-VEGF. Additional studies are required to evaluate the safety and efficacy of brolucizumab for MNV in vitrectomized eyes.