Design optimization of hydrodynamic cavitation (HC) was performed for the sake of maximally extracting internal lipids directly from wet microalgae. Different types of orifice plates (alpha = 2.5-10%; beta = 1-10%) were designed for a HC system and examined in terms of cavity formation; and cavitation effect was demonstrated by way of lipid extraction from microalgae. Basic operating parameters of HC, such as flux, flow rate, and the number of rotation, were examined and based on them, the upper and lower limits of cavitation number identified to be 3.37 +/- 0.01 (alpha = 2.5% and beta = 1%) and 1.01 +/- 0.00 (alpha = 7.5% and beta = 1%), respectively. The maximum lipid extraction (46.0 +/- 3.7%) was obtained at 5% of both alpha and beta. A low beta value resulted in high vapor pressure, which has a crucial effect on the cell disruption caused by the creation and extinction of cavities. Also, the number of treatment per minute through the orifice proved to be a crucial factor for cell disruption. On the other hand, a high alpha value caused a surge pressure driven by violent fluctuation of flow. The cavitation effects of HC were able to be well visualized in terms of pressure variation using CFD. This study showed that the HC is indeed a very promising cell disruptor and its effectiveness can be further enhanced by way of design optimization.