The performance of matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) is frequently compromised by the heterogeneous distribution of matrix and analyte deposits on the target plate arising during the conventional drop-drying sample preparation procedure. It was recently shown that this so-called coffee stain effect can be suppressed by exciting evaporating complex fluids throughout the drying process using AC-electrowetting. Here, we demonstrate that electrowetting-assisted drying of solutions of common MALDI matrix materials and a variety of common low molecular weight pharmaceutical molecules indeed leads to substantially smaller and more homogeneous sample spots on special electrowetting-functionalized e-MALDI target plates. The improved spot quality enables 2–30× enhanced MALDI-MS signals along with substantial reductions of the typical lateral variations of the MALDI-MS. The latter largely eliminates the time-consuming need to search for “sweet spots”.