Two-dimensional (2D) MoS2, part of the transition metal dichalcogenides family, has emerged as a promising candidate for wearable strain sensors owing to its unique attributes, including mechanical flexibility, low toxicity, tunable and high electrical properties. MoS2-based sensors exhibit higher gauge factors (∼760 for monocrystalline, ∼56.5 for polycrystalline) and a lower limit of detection than conventional metal sensors. We report an advanced strain sensor with ultra-high sensitivity to minute deformations, exploiting a three-dimensional nanostructured-2D MoS2 (3DN-MoS2) with an arch-like configuration. The nanoarchstructured MoS2-based strain sensor (NaM-SS) achieves exceptional gauge factors, exceeding 1500 for tensile strain, using 3DN-MoS2 sensing material in conjunction with a poly-dimethylsiloxane support. This piezo-resistive sensor, fabricated through an eco-friendly and straightforward process, exhibits remarkable gauge factors at three levels: 1500 (ε < 0.55 %), 13,500 (0.55 %< ε ≤ 0.75 %), and 37,000 (0.75 % < ε ≤ 1.2 %). The sensor’s limit of detection stands at a subtle tensile strain ε of 0.02 %. Furthermore, its feasibility is validated by its ability to monitor various human physical motions, including eye blinking, blood pulsation, and muscle activity. Our findings indicate significant potential for precision strain sensors in applications requiring ultra-high sensitivity, such as detecting subtle biomedical signals, meticulous machinery control, and structural health monitoring.