Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by a high-fat diet (HFD). This study shows that HFD reduces spontaneous physical activity (SPA) and NEAT, while orexin neuron activation via DREADDs restores NEAT to control levels. Mice on HFD spent more time inactive and less time eating compared to those on a standard chow diet. Following a meal, HFD mice were more likely to remain inactive. NEAT was lower in HFD mice, but increased to control levels after orexin neuron activation. Food intake was similar between HFD and chow groups, but chow-fed mice expended more energy per unit of SPA. These results suggest that HFD reduces SPA and NEAT, and increases inactivity after meals. Orexin activation via DREADDs increased NEAT, indicating that orexin neurons play a key role in regulating NEAT. The study highlights the therapeutic potential of orexin activation in counteracting the negative effects of HFD on energy expenditure. The findings have implications for understanding how changes in physical activity contribute to obesity.Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by a high-fat diet (HFD). This study shows that HFD reduces spontaneous physical activity (SPA) and NEAT, while orexin neuron activation via DREADDs restores NEAT to control levels. Mice on HFD spent more time inactive and less time eating compared to those on a standard chow diet. Following a meal, HFD mice were more likely to remain inactive. NEAT was lower in HFD mice, but increased to control levels after orexin neuron activation. Food intake was similar between HFD and chow groups, but chow-fed mice expended more energy per unit of SPA. These results suggest that HFD reduces SPA and NEAT, and increases inactivity after meals. Orexin activation via DREADDs increased NEAT, indicating that orexin neurons play a key role in regulating NEAT. The study highlights the therapeutic potential of orexin activation in counteracting the negative effects of HFD on energy expenditure. The findings have implications for understanding how changes in physical activity contribute to obesity.