Background: To evaluate the effects of a preservative-free artificial tear formulation containing trehalose, sodium hyaluronate, and N-acetyl-aspartyl-glutamate (NAAGA) on ocular surface parameters and quality of life in patients with primary open-angle glaucoma (POAG) treated with preserved versus preservative-free prostaglandin analogues. Methods: For this prospective, observational clinical study, thirty-eight patients (76 eyes) with POAG receiving stable topical prostaglandin therapy were enrolled and divided into two groups: preserved prostaglandins (Group 1, n = 44) and preservative-free prostaglandins (Group 2, n = 32). All patients received adjunctive preservative-free artificial tears (trehalose, sodium hyaluronate, NAAGA) three times daily for one month. Assessments at baseline (T0) and 1 month (T1) included best-corrected visual acuity (BCVA), intraocular pressure (IOP), contrast sensitivity, Schirmer test, tear break-up time (BUT), Efron grading scale, Ocular Surface Disease Index (OSDI), visual field (VF) indices (Mean Deviation (MD), Pattern Standard Deviation (PSD), Visual Field Index (VFI)), and quality of life (QoL) measured using Visual Analogue Scales (VAS). Results: After 1 month, both groups demonstrated significant improvement in ocular surface parameters. Schirmer test increased by approximately 4–5 mm (p = 0.001 in both groups), and BUT improved by 5 s (p = 0.001 in both groups). OSDI scores significantly decreased (Group 1: –18.5; Group 2: –23; p = 0.001 for both), and Efron grading significantly improved (p = 0.001 in both groups). Artificial tears-related QoL markedly increased in both groups (p = 0.001), while pathology-related QoL remained unchanged. IOP showed a modest but significant reduction in both groups (Group 1 p = 0.011; Group 2 p = 0.003), without intergroup differences. VFI significantly improved in both groups from T0 to T1 (Group 1 p = 0.013; Group 2 p = 0.04). Group 1 also showed an improvement in terms of PSD (p = 0.025). Conclusions: Adjunctive treatment with preservative-free artificial tears containing trehalose, sodium hyaluronate, and NAAGA significantly improved tear film stability VF indexes, ocular surface signs and symptoms, and patient-reported QoL in POAG patients treated with prostaglandins, regardless of preservative status. Routine ocular surface optimization should be considered an integral component of comprehensive glaucoma management.