Objective To evaluate the efficacy and safety of levetiracetam (LEV) monotherapy for new-onset epilepsy in middle-aged and elderly patients (aged ≥40 years). Methods PubMed, Embase, Cochrane Library, CNKI, and Wanfang were searched through December 31, 2025 for RCTs comparing LEV versus other antiseizure medcations (ASMs) monotherapy in patients aged ≥40 years. Cochrane RoB 2.0 and random-effects models (DerSimonian-Laird) were used to assess bias and pool risk ratios (RR). Results A total of 9 randomized controlled trials (RCTs) were enrolled, involving 1 152 participants (575 in the LEV group and 577 in the control group). The participants were aged 40–95 years with a follow-up duration of 6–58 months. The control medications included oxcarbazepine (OXC, 4 trials), carbamazepine (CBZ, 3 trials), and controlled-release carbamazepine (CR-CBZ, 2 trials). Pooled overall response rate analysis across all 9 trials demonstrated superior efficacy in the LEV group compared with the control group [relative risk (RR) = 1.192, 95% confidence interval (CI) (1.131, 1.257), Z=6.57, P<0.001, I2=0.0%]. Subgroup analyses yielded consistent results: LEV vs. OXC (4 trials, RR=1.185, 95%CI (1.093, 1.285), I2=0.0%) and LEV vs. CBZ/CR-CBZ (5 trials, RR=1.209, 95%CI (1.111, 1.316), I2=27.9%). The 12-month seizure-free rate was assessed in 5 trials with 845 subjects, showing a significantly higher rate in the LEV group [RR=1.130, 95%CI (1.023, 1.248), P=0.016, I2=2.5%]. The adverse event rate, analyzed based on 5 trials enrolling 803 patients, was markedly lower in the LEV group [RR=0.586, 95%CI (0.388, 0.887), P=0.011, I2=45.4%]. Sensitivity analyses by sequential exclusion of individual studies confirmed stable pooled outcomes. Conclusion LEV monotherapy shows better efficacy and fewer adverse events than traditional ASMs in middle-aged and elderly patients with new-onset epilepsy. Confirmatory international multicenter RCTs are needed.