This prospective study aimed to assess the impact of topical latanoprost 0.005% treatment on the microvasculature of the macula and optic nerve head (ONH) in primary open-angle glaucoma (POAG). Fifty-seven eyes of 31 subjects were enrolled. ONH whole-image (wiVD), peripapillary (ppVD), and macular vascular density (VD) parameters were measured using optical coherence tomography angiography before treatment, at the 1st month, and at the 3rd month of treatment. There was a significant reduction in IOP post treatment, with a decrease of 17.0 ± 2.3 mmHg in the 1st month and 16.3 ± 2.5 mmHg in the 3rd month (P < 0.001 for both). ONH wiVD and ppVD significantly increased at the post-treatment 1st month (P = 0.001 for both) but decreased by the 3rd month, returning to baseline levels (P < 0.001 for both), indicating a return to pre-treatment levels (P > 0.05 for both). Similarly, macular wiVD and perifoveolar VD (pefVD) increased significantly at the 1st month (P = 0.013 and P < 0.001, respectively) but returned to baseline by the 3rd month (P < 0.001 for both). No significant difference was observed between before-treatment and post-treatment 3rd month regarding the macular wiVD and pefVD (P > 0.05 for both). Deep capillary plexus and foveal avascular zone parameters did not change during follow-up (P > 0.05 for both). The initial increase in ONH and peripapillary VD, as well as macular VD, is attributed to the acute reduction in IOP from topical latanoprost 0.005%. However, the diminishment of sustained differences by the 3rd month indicates adaptation of the ONH and retinal microvasculature to decreased IOP through compensatory mechanisms.