<p>Microneedle-based interstitial fluid sensors have emerged as a powerful tool for continuous biochemical monitoring. However, their practical application has been limited by strain-induced performance degradation due to mechanical instability at the interface between soft substrates and rigid microneedles. Here, we present a fully stretchable, strain-insensitive microneedle-based biochemical sensing platform with an integrated wireless optical monitoring system. The device features a monolithic structure composed entirely of siloxane-based materials, where microneedles are covalently bonded to the elastomeric substrate, ensuring robust structural integrity under mechanical deformation. The sensor maintains a glucose sensitivity of 0.429 mM⁻¹ even at 80% tensile strain, with performance variations below 5%, significantly outperforming conventional strain-sensitive microneedle sensors. Furthermore, the wireless optical monitoring system utilizing near-infrared light-emitting diodes enables real-time biomarker measurement through optical data captured by a smartphone camera, with high quantification accuracy (R² = 0.999). This platform was adapted for the detection of multiple biomarkers, including glucose, lactate, and urate, demonstrating its broad applicability for biochemical monitoring. In vivo testing in an anesthetized rat model successfully tracked continuous glucose fluctuations over 4 h, with results showing a strong correlation (R² = 0.94) with commercial glucometer readings.</p>