AbstractWearable bioelectronics represents a significant breakthrough in healthcare settings, particularly in (bio)sensing which offers an alternative way to track individual health for diagnostics and therapy. However, there has been no notable improvement in the field of cancer, particularly for skin cancer. Here, a wearable bioelectronic patch is established for transdermal sensing of the melanoma biomarker, tyrosinase (Tyr), using a microneedle array integrated with a surface‐bound chemo‐responsive smart probe to enable target‐specific electrochemical detection of Tyr directly from human skin tissue. The results presented herein demonstrate the feasibility of a transdermal microneedle sensor for direct quantification of enzyme biomarkers in an ex vivo skin model. Initial performance analysis of the transdermal microneedle sensor proves that the designed methodology can be an alternative for fast and reliable diagnosis of melanoma and the evaluation of skin moles. The innovative approach presented here may revolutionize the landscape of skin monitoring by offering a nondisruptive means for continuous surveillance and timely intervention of skin anomalies, such as inflammatory skin diseases or allergies and can be extended to the screening of multiple responses of complementary biomarkers with simple modification in device design.