The catalyst layer of the cathode is arguably the most critical component of low-temperature fuel cells and carbon dioxide (CO2) electrolysis cells because their performance is typically limited by slow oxygen (O2) and CO2 reduction kinetics. While significant efforts have focused on developing cathode catalysts with improved activity and stability, fewer efforts have focused on engineering the catalyst layer structure to maximize catalyst utilization and overall electrode and system performance. Here, we study the performance of cathodes for O2 reduction and CO2 reduction as a function of three common catalyst layer preparation methods: hand-painting, air-brushing, and screen-printing. We employed ex-situ X-ray micro-computed tomography (MicroCT) to visualize the catalyst layer structure and established data processing procedures to quantify catalyst uniformity. By coupling structural analysis with in-situ electrochemical characterization, we directly correlate variation in catalyst layer morphology to electrode performance. MicroCT and SEM analyses indicate that, as expected, more uniform catalyst distribution and less particle agglomeration, lead to better performance. Most importantly, the analyses reported here allow for the observed differences over a large geometric volume as a function of preparation methods to be quantified and explained for the first time. Depositing catalyst layers via a fully-automated air-brushing method led to a 56% improvement in fuel cell performance and a significant reduction in electrode-to-electrode variability. Furthermore, air-brushing catalyst layers for CO2 reduction led to a 3-fold increase in partial CO current density and enhanced product selectivity (94% CO) at similar cathode potential but a 10-fold decrease in catalyst loading as compared to previous reports.