Objective To observe the protection effects of ultrasonic microbubbles combined with memantine on rat retinal ganglion cells (RGCs) after optic nerve injury. Methods Forty Sprague-Dawley adult male rats were randomly divided into normal control group (group A), sham operation group (group B), blank control group (group C), memantine group (group D) and memantine and ultrasonic microbubbles group (group E), 8 rats in each group. Then A - E groups were randomly divided into 1 week subgroup and 2 weeks subgroup after the optic nerve injury, 4 rats in each subgroup. Group A had no interference treatment. The optic nerves in group B eyes were exposed but not clamped. Normal saline was injected into the vitreous, and those eyes were immediately radiated with ultrasound. The optic nerves in Group C - E were exposed and clamped to establish the optic nerve clamped models. Normal saline was injected into the vitreous of group C eyes; memantine was injected into the vitreous of group D eyes; ultrasonic microbubble and memantine was orderly injected into the vitreous of group E eyes and those eyes were immediately radiated with ultrasound. One week and 2 weeks after the optic nerve injury, RGC was labeled by retrograde fluorogold to count the RGC number; flash visual evoked potential (F-VEP) was used to record the incubation period and amplitude of P100 wave; fluorescence microscopy was used to observe the pathological morphology change of retinal cell. Results There were goldlabeled RGCs on the retina of group A-E. The difference of RGC count was not statistically significant between group A and B (q=0.018, 0.011; P=0.986, 0.873). Compared to group A, the RGC count in group C-E were decreased significantly (F=85.944, P=0.012). The RGC count in group D was significantly higher than that in group C (q=1.721, 1.924; P=0.043, 0.037). The RGC count in group E was significantly higher than that in group C and D (q=1.128, 1.482, P=0.027, 0.008; q=1.453, 1.855, P=0.031, 0.010).F-VEP showed that there was no statistically significant difference of incubation period and amplitude of P100 wave between group A and B (q=0.008, 0.019,P= 0.981, 0.946; q=0.072, 0.052, P=0.737, 0.851). Compared to group A, the incubation period were lengthened and the amplitude were decreased in group C- E with statistically significant (F=134.312, 106.312; P=0.017, 0.009). Observed under the electron microscope, the retinal structure of group A, B eyes was normal, but there were varying degrees of edema and thickening, RGC loss in group C-E eyes. Conclusions Memantine and ultrasonic microbubble can inhibit the rat RGC loss after optic nerve injury, and improve the visual function.