Background: Optical coherence tomography angiography (OCT-A) provides quantitative assessment of retinal and peripapillary microvasculature and has emerged as a promising tool for glaucoma diagnostics. However, its sensitivity for detecting early glaucomatous progression over short intervals remains uncertain. This study evaluated cross-sectional and short-term longitudinal OCT-A vessel density (VD) metrics in primary open-angle glaucoma (POAG) and explored their relationships with structural (RNFL) and functional (MD) measures. Methods: Sixty eyes (30 POAG, 30 controls) underwent baseline and 6-month examinations including intraocular pressure (IOP), standard automated perimetry (SAP), structural OCT, and OCT-A (RTVue XR Avanti; AngioVue). Parameters analyzed included peripapillary VD (PP-VD), parafoveal VD (PF-VD), foveal avascular zone (FAZ) metrics, FD-300, and RNFL thickness. Between-group comparisons used t-tests or Mann–Whitney U tests. Effect sizes (Cohen’s d), 95% confidence intervals (CI), and ANCOVA models (adjusted for baseline, age, and sex) were included. Longitudinal change was defined as Δ = 6 months − baseline. Pearson correlations evaluated structure–vascular associations. Results: At baseline, POAG eyes showed significantly lower PP-VD, PF-VD, thinner RNFL, and worse MD (all p < 0.001). Strong correlations were observed between RNFL and PP-VD (r ≈ 0.7). Over 6 months, glaucoma eyes showed small but statistically significant reductions in RNFL (Δ = −1.04 µm), MD (Δ = −0.10 dB), and PP-VD (Δ = −0.57%), whereas controls remained stable. However, the absolute OCT-A changes were small and largely within the known range of test–retest variability. ANCOVA demonstrated a significant adjusted group effect only for PP-VD (B = −1.22%, 95% CI −1.53 to −0.90; p < 0.001). Conclusions: OCT-A demonstrated clear cross-sectional differences between POAG and controls and strong structure–vascular associations. However, with only two measurements over a 6-month interval, the study cannot distinguish true glaucomatous progression from physiological or device-related variability. Short-term changes should therefore be interpreted cautiously. PP-VD remains the most robust and consistent OCT-A parameter, but larger, longer, and prospectively powered studies are required to validate OCT-A as a reliable biomarker for progression.

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