Epilepsy is a common neurological disease that seriously affects the quality of life of patients. There are many clinical drugs for treatment. Levetiracetam and lacoxamide have attracted much attention in recent years. This study focuses on comparing the efficacy and safety of the 2 treatments for epilepsy, in order to provide strong support for clinical precision medicine. In this retrospective study, we collected the case data of 82 patients. Eighty-two patients with epilepsy admitted to our hospital from March 2022 to February 2023 were selected and evenly divided into levetiracetam group (41 cases) and lacoxamide group (41 cases) by different treatment method. The whole treatment cycle lasted 24 weeks. The effectiveness measures included seizure frequency, seizure duration, electroencephalogram (EEG) improvement, cognitive function score, and quality of life scale score. The safety assessment included the incidence, type, and severity of adverse reactions. In terms of effectiveness, the seizure frequency of levetiacetam group after treatment was reduced by about (42.0 ± 3.5) % (P < .05), the seizure duration was shortened by (35.0 ± 2.8) seconds (P < .05), and the normalization ratio of EEG reached (38.0 ± 4.2) % (P < .05). Compared with before treatment, the cognitive function score was increased by (12.0 ± 1.5) points (P < .05), the quality of life scale score was increased by (18.0 ± 2.2) points (P < .05). In lacosamine group, the seizure frequency was decreased by about (39.0 ± 3.2) % (P < .05), the seizure duration was shortened by (30.0 ± 2.5) s (P < .05), and the improvement rate of EEG was (35.0 ± 3.8) % (P < .05). The cognitive function score increased (10.0 ± 1.3) points (P < .05), and the quality of life scale score increased (15.0 ± 2.0) points (P < .05). Both levetiracetam and lacoxamine show significant effectiveness in the treatment of epilepsy, which can effectively control seizure frequency and duration from multiple dimensions, improve EEG, and enhance patients' cognition and quality of life. In terms of safety, the characteristics of adverse reactions were different, and levetiracetam was generally well tolerated.