A recently designed packing sheet Winpak was assembled with catalysts in a modular catalytic structured packing (MCSP) column. A combined mesoscalemicroscale methodology was used to analyze and determine the pressure drop mechanism in the MCSP. The proposed methodology differentiates the pressure drop into six different principles, which was determined and compared using computational fluid dynamics (CFD). The three major causes are gas flow confluence and diffluence through the packing windows, the sudden change in the effective gas channel area and the wall effect. Inspired by constructal theory, the height of packing sheets loaded with catalysts was reduced, which resulted in a less abrupt gas channel contraction and expansion at the packing layer junction and more favorable for the undisturbed gas flow. The optimized overall pressure drop was reconstructed in Fluent and was validated by both dry and irrigated packing experiments. Furthermore, irrigated packing experiments were also conducted. Result comparisons reveal that the proposed optimization method is reliable and accurate. This methodology is shown to be significant in the optimization of Winpak-based MCSP.