The ventral pallidum (VP) is involved in the regulation of a variety of behaviors such as motor, reward, and behavioral motivation, and the ability to perform these functions properly is dependent on a high degree of wakefulness. It is unknown whether VP CaMKIIa-expression (VP) neurons also have a role in sleep-wake regulation and related neuronal circuit mechanisms. In the present experiment, we first used in vivo fiber photometry to find the population activity of VP neurons which increased during the transitions from non-rapid-eye movement (NREM) sleep to wakefulness and NREM sleep to rapid-eye-movement (REM) sleep, with decreased during the transitions from wakefulness to NREM sleep. Then chemogenetic activation of VP neurons induced an increase in wakefulness that lasted for 2 h. Mice that were exposed to short-term optogenetic stimulation woke up quickly from stable NREM sleep, and long-term optogenetic stimulation maintained wakefulness. In addition, optogenetic activation of the axons of VP neurons in the lateral habenula (LHb) also facilitated the initiation and maintenance of wakefulness and mediated anxiety-like behavior. Finally, the method of chemogenetic inhibition was employed to suppress VP neurons, and yet, inhibition of VP neuronal activity did not result in an increase in NREM sleep and a decrease in wakefulness. Overall, our data illustrate that the activation of VP neurons is of great importance for promoting wakefulness.