Antiretroviral drugs are associated with increased body weight and metabolic disorders. Fat gain and insulin resistance are commonly associated with abdominal obesity in people with HIV (PWH). There is currently an open ongoing discussion about how antiretroviral therapy affects body weight and its significance in hunger-satiety circuit alteration. Until now, the impact of the drug on this circuit has not been explored. This study aimed to assess the hormones involved in appetite and satiety regulation in the serum and hypothalamus after efavirenz (EFV) administration in mice. EFV (10 mg/kg) and distilled water (1.5 μL/kg) (control group) were orally administered for 36 days to CD1 mice. Body weight and food intake were determined throughout treatment. At the end of the treatment, the metabolic profile (glucose, triglycerides, cholesterol) was assessed, and leptin, soluble receptor of leptin (sOB-R), and ghrelin were measured in serum; moreover, we evaluated the expression of growth hormone secretagogue receptor 1a (GHS-R1a), neuropeptide Y receptor 1 (NPYR1), and leptin in the hypothalamus, and a sucrose preference test (SPT) was conducted. Outcomes showed an increase in serum ghrelin and the expression of GHS-R1a and NPYR1 receptors in the hypothalamus, coinciding with an increase in appetite and preference for sucrose in mice in the EFV group. Furthermore, serum leptin, sOB-R, and the free leptin index (FLI) showed that hunger is not related to a lack of satiety. Despite increased food intake, a reduction in body weight was observed, and triglyceride and cholesterol levels were increased. According to our findings, mice treated with EFV showed a decrease in body weight, despite increased food intake resulting from appetite stimulation, which is caused by specific compounds, hormones, and neural signals acting on the brain's hunger centres, primarily in the hypothalamus, promoting eating behaviours. However, further studies are necessary to investigate the mechanisms of EFV's effects on energy expenditure.