Abstract Emerging classes of wearable microfluidic sensors of eccrine sweat enable non‐invasive and real‐time monitoring of health status in applications that range from sports to worker safety, environmental exposures, and medical care. Opportunities for improving the performance of these systems include those in colorimetric detection of biochemical species with high accuracy across a wide dynamic range, in efficient collection of sweat and local measurements of sweat loss across a broad spectrum of sweat rates, and in an expanded set of biomarker targets. This paper introduces concepts in 3D microfluidic structures, surface chemistry, interface design, and colorimetric chemical reagents that address these opportunities. Demonstrations involve accurate quantification of sweat rate and total loss over a wide range, as well as precise colorimetric sensing of chloride, xanthine, and creatinine, as biomarkers associated with electrolyte balance, purine metabolism, and kidney function, respectively. Benchtop evaluations confirm high sensitivity and reproducibility, while on‐body trials illustrate reliable biomarker tracking in response to dietary intake and physiological activity. These ideas and chemistries expand the possibilities in sweat‐based diagnostic strategies, in strategies that have the potential to align with established, high‐volume manufacturing practices for commercial production.