Purpose: The aim of the study was to assess the early retinal structural changes due to hydroxychloroquine (HCQ) use and its impact on visual acuity (VA) of patients with systemic lupus erythematosus (SLE). Patients and Methods: The study was conducted as a case-control study that included 60 eyes of 30 SLE patients treated with HCQ compared with 50 eyes of 25 healthy individuals. Patients were kept on 200 or 400 mg as daily maintenance dose. SLE patients were subgrouped into patients with normal VA and patients with decreased VA. All participants were assessed by the optical coherence tomography (OCT), and early structural abnormalities were recorded. The main outcomes and measures were best-corrected VA, drug exposure time, central macular thickness (CMT), inner segment-outer segment (IS-OS) junction disruption, ganglion cell complex † (GCC†, ganglion cell layer + inner plexiform layer), ganglion cell complex †† (GCC††, nerve fiber layer + GCC†), and peripapillary retinal nerve fiber layer. The characteristics of HCQ retinal toxicity were correlated to VA. Results: All OCT parameters were found to be significantly lower (p < 0.001) in HCQ patients with decreased VA than in controls. Patients receiving a daily dose of 400 mg had lower (p < 0.05) parameters than those receiving 200 mg. Patients with IS-OS disruption had lower CMT, GCC †, and GCC †† than those without (p < 0.05). VA was significantly correlated (p < 0.05) with CMT and drug exposure time. Conclusions: The HCQ use caused OCT changes that precede clinically visible retinopathy and might be associated with slight VA reduction. Screening with OCT of patients receiving HCQ is essential to detect early vision loss.