Vagus nerve stimulation (VNS) is used for treating refractory epilepsy and major depression. While the impact of this treatment on seizures has been established, its impact on human cognition remains equivocal. The goal of this study is to elucidate the immediate effects of vagus nerve stimulation on attention, cognition, and emotional reactivity in patients with epilepsy. Twenty patients (12 male and 8 female; 45 ± 13 years old) treated with VNS due to refractory epilepsy participated in the study. Subjects performed a computer-based test of executive functions embedded with emotional distractors while their brain activity was recorded with electroencephalography. Subjects' cognitive performance, early visual event-related potential N1, and frontal alpha asymmetry were studied when cyclic vagus nerve stimulation was on and when it was off. We found that vagus nerve stimulation improved working memory performance as seen in reduced errors on a subtask that relied on working memory, odds ratio (OR) = 0.63 (95% confidence interval, CI [0.47, 0.85]) and increased N1 amplitude, F(1, 15) = 10.17, p = .006. In addition, vagus nerve stimulation resulted in longer reaction time, F(1, 16) = 8.23, p = .019, and greater frontal alpha asymmetry, F(1, 16) = 11.79, p = .003, in response to threat-related distractors. This is the first study to show immediate improvement in working memory performance in humans with clinically relevant vagus nerve stimulation. Furthermore, vagus nerve stimulation had immediate effects on emotional reactivity evidenced in behavior and brain physiology.