Aims: To review the findings in the professional literature on unexplained loss of visual acuity (VA) in patients with silicone oil (SO) tamponade and post-removal, and assess the efficacy and safety of citicoline as a neuroprotective agent on anatomical changes and visual function in patients undergoing 25-gauge pars plana vitrectomy (PPV) for rhegmatogenous retinal detachment with large/multiple tears (macula-on/off). Materials and Methods: We studied 96 eyes, 64 receiving citicoline (5 ml orally 3x daily) after PPV with SO tamponade, performed from 01.01.2023 to 30.06.2023 at the Eye Clinic of SZU and UNB. Best corrected visual acuity (BCVA) was measured using ETDRS charts, and changes in the retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) were assessed using OCT at 1, 3 and 6 months. Complications were monitored and results analyzed statistically. Results: BCVA improved (citicoline: 19 to 48 letters; non-citicoline: 13 to 42 letters, p < 0.001), with better results in the citicoline group (p < 0.01). Intraocular pressure remained normal (10–21 mmHg), with a difference at 3 months (19 vs. 17 mmHg, p < 0.05). RNFL thickness decreased in T and S quadrants (T quadrant: 55 to 45 µm with citicoline, 52 to 41 µm without, p < 0.001), but was higher with citicoline (T quadrant: 50 vs. 44 µm, p < 0.01). GCL thickness initially decreased, then increased (T quadrant: 84 to 82 to 88 µm with citicoline, p < 0.0033), with higher values in the citicoline group (p < 0.0125). Citicoline demonstrated stronger neuroprotection in the GCL (GEE, p < 0.05). Conclusion: Citicoline is a promising neuroprotective agent which potentially reduces loss of VA upon the use of SO tamponade, with positive impacts on the RNFL, GCL and visual function. Further randomized trials are required.