Purpose Reducing the mean age of puberty onset in recent years has crucial public health, clinical, and social implications. This study aimed to evaluate the serum levels of appetite-related peptides (leptin, ghrelin, nesfatin-1, and orexin-A) and anthropometric data in girls with premature thelarche (PT). Methods We enrolled 44 girls aged 4-8 years diagnosed with PT and 33 age-matched healthy girls as controls. The demographic data of the girls were obtained using a questionnaire. Anthropometric data were measured and fasting blood samples were collected. Results Body weight, height, body mass index (BMI), body fat mass, and basal metabolic rate (BMR) were higher in the PT group than in the control group (p < 0.05). Serum leptin (p < 0.001), nesfatin-1 (p = 0.001), and orxein-A (p < 0.001) levels were significantly higher in the PT group than in healthy controls. However, there were no significant differences in the serum ghrelin levels between the groups (p > 0.05). The results of multivariate logistic regression revealed that serum leptin level (OR (95% CI): 42.0 (10.91, 173.06), p < 0.001), orexin-A (OR (95% CI): 1.14 (1.04, 1.24), p = 0.006), and BMI for age z-score (OR (95% CI): 6.97 (1.47, 33.4), p = 0.014) elevated the risk of incidence of PT at 4-8 girls. Conclusion These results suggest that in addition to serum leptin levels, serum orexin-A and nesaftin-1 can take part in the initiation of PT. Few studies have investigated the relationship between nesfatin-1 and orexin-A levels and age at onset of puberty; hence, it should be a subject for future studies.