Obesity is a global health crisis strongly linked to increased risk of type 2 diabetes, cardiovascular diseases, and other metabolic disorders. Glucagon-like peptide-1 (GLP-1) has emerged as an effective macromolecular therapeutic agent for weight management. This study addressed obesity management from three distinct perspectives: enhancing drug dispersion and bioavailability through a novel drug delivery device, extending drug half-life by developing sustained-release formulations, and sustaining the weight loss through implementation of structured dietary protocols. A new technology, micro-needle jet injection (MNJI) was developed to deliver both standard semaglutide formulations and highly viscous sustained-release formulations, achieving 100% subcutaneous delivery with predictable results. Modulation of MNJI parameters enabled the generation of various dispersion profiles, resulting in higher bioavailability compared to both needle injection (NI) and needle-free jet injection (NFJI). Sustained-release formulations, effectively administered via MNJI, exhibited higher bioavailability than the non-sustained release formulation, and positively impacted weight management efficacy in two distinct ways. First, a single injection achieved the same weight loss as five daily administrations of non-sustained release formulation. Second, a subsequent injection of the sustained-release formulations resulted in a further body weight reduction to 18%, contrasting sharply with the plateau at 13% observed in the standard formulation administered daily ( < 0.05). Finally, dietary management, particularly time-restricted feeding, successfully maintained weight loss at ∼18% below baseline levels. Collectively, the combination of MNJI delivered sustained-release formulations and structured dietary protocols offers a promising and patient-friendly strategy for long-term obesity management, improving both adherence and therapeutic outcomes.