Obesity is a major health problem worldwide and the strongest risk factor for diabetes, the fifth leading risk for global deaths. Although body fat can be reduced through diet and lifestyle adjustments, pharmacotherapies are required for long-term weight loss management in obese patients. Phentermine, orlistat and liraglutide are the only three drugs approved by the Therapeutic Goods Administration to treat obesity in Australia. Despite being effective they show significant side effects and were not explicitly designed to treat obesity. Thus, treatment of obesity based on targeted therapy with minimal adverse side effects represents a significant unmet clinical need. In general, peptides can fill this gap, offering greater efficacy, selectivity, and specificity than small molecules drugs. Peptides are the smallest functional part of natural proteins, and their degradation products are amino acids, thus minimising the risk of toxicity and potential side effects. Here we report the design of a new generation of peptide-based therapeutics that target white adipose tissues (WAT) with great potential for reducing body weight. We evaluate a series of multi-functional anti-obesity peptide by fusing a helical peptide warhead with a WAT-targeting motif. These two motifs work together to target the destruction of white adipocyte mitochondria. This study provides an insight into the rational design and development of multi-functional anti-obesity peptide therapeutics that are effective, stable and non-toxic with good pre-clinical safety profiles. We demonstrate that this novel approach has resulted in a potent multi-functional drug lead that could regulate the adipogenesis process by reducing overcrowded adipocyte expansion and with significant body weight reduction in a high-fat diet-induced mouse model (daily subcutaneous injection, 4 weeks, >30% loss in WAT, and >20% loss in overall body weight). This study provides a promising approach for developing anti-obesity peptide and highlights its potential to treat metabolic disorders for treating obesity.