Objective: To evaluate the effect of minocycline hydrochloride on the survival of retinal ganglion cells (RGCs) in glaucomatous rat eyes and rat eyes after optic nerve transection (ONT). Methods: The effect of intraperitoneal injections of minocycline at dosages of 15 mg/kg per day, 22 mg/kg per day, and 45 mg/kg per day was evaluated and compared with saline in ONT (n = 174) and experimental glaucoma (n = 51). Results: The mean ± SEM survival rate of RGCs 1 week after ONT was significantly higher with minocycline at dosages of 15 mg/kg per day (36% ± 3%; n = 9; P= .04), 22 mg/kg per day (44% ± 2%; n = 15; P = .001), and 45 mg/kg per day (39% ± 3%; n = 10; P = .008) compared with saline (29% ± 2%; n = 28). Minocycline at a dosage of 22 mg/kg per day was also significantly neuroprotective compared with saline 2 weeks after ONT (mean ± SEM survival rate, 5% ± 1% vs 3%± 0.4%, respectively; n = 20 [10 rats in each group]; P=.03). In experimental glaucoma, the mean ± SEM percentage of RGCs after 4 weeks was 84% ± 4% in the minocycline group (n = 15) compared with 65% ± 4% in the saline group (n = 18) (P = .003). Apoptosis of RGCs was significantly delayed by minocycline 4 days and 1 week after ONT. Conclusion: Minocycline significantly enhances the survival of RGCs after ONT and in experimental glaucoma by delaying the apoptosis pathway. Clinical Relevance: The safety record of minocycline and its ability to penetrate the blood-brain barrier suggest that this drug is a promising neuroprotective drug for optic nerve injuries.