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Microfluidic systems for medical applications necessitate reliable, wide flow range, and low leakage microvalves for flow path control. High design complexity of microvalves increases the risk of possible malfunction. We present a normally open microvalve based on energy-efficient piezoelectric actuation for high closing forces and micromachined valve seat trenches for reliable valve operation. A comprehensive investigation of influencing parameters is performed by extensive fluidic 3D finite element simulation, derivation of an analytical closed state leakage rate model, as well as fabrication and test of the microvalve. Additional valve seat coating and a high force actuator are introduced for further leakage reduction. The microvalve has a wide-open flow range as well as good sealing abilities in closed state. Extensive fatigue tests of 1 × 106 actuation cycles show that additional coating of the valve seat or increased actuator strength promote sealing performance stability. Analytical calculations of leakage are suitable to estimate experimentally obtained leakage rates and, along with computational fluidic dynamic (CFD) simulations, enable future microvalve design optimization. In conclusion, we demonstrate that the presented normally open microvalve is suitable for the design of safe and reliable microfluidic devices for medical applications.