Abstract The objective of this study was to explore the protective effects of hydroxy fullerenes (HFs) on cognitive function in rats with temporal lobe epilepsy (TLE) and to elucidate the underlying mechanisms. Eighteen Sprague-Dawley (SD) rats were randomly selected and administered pilocarpine (50 mg/kg) intraperitoneally to establish a TLE model, and were then randomly assigned to the TLE group and the TLE + HFs group. An additional nine SD rats were served as a normal control group (CON group). The Morris water maze (MWM) test was utilized to assess the spatial learning and memory capabilities of the rats. Nissl staining was employed to observe the survival neurons in the CA1 and CA3 regions. In addition, the ultrastructure of synapses in the CA1 region was examined using transmission electron microscopy (TEM). The expressions of postsynaptic densitin-95 (PSD-95) and synaptophysin (SYP) in the hippocampus were detected via western blotting. The findings revealed that compared to the CON group, the TLE group exhibited significantly prolonged escape latency, reduced platform crossing frequency, and shortened time spent in the target quadrant. The number of surviving neurons in the CA1 and CA3 regions and the expression of PSD95 and SYP protein were significantly decreased (P