Hydrodynamic cavitation is considered an effective tool to be used in different applications, such as surface cleaning, ones in the food industry, energy harvesting, water treatment, biomedical applications, and heat transfer enhancement. Thus, both characterization and intensification of cavitation phenomenon are of great importance. This study involves design and optimization of cavitation on chip devices by utilizing wall roughness elements and working fluid alteration. Seven different microfluidic devices were fabricated and tested. In order to harvest more energy from cavitating flows, different roughness elements were used to decrease the inlet pressure (input to the system), at which cavitation inception occurs. The implemented wall roughness elements were engineered structures in the shape of equilateral triangles embedded in the design of the microfluidic devices. The cavitation phenomena were also studied using ethanol as the working fluid, so that the fluid behavior differences in the tested cavitation on chip devices were explained and compared. The employment of the wall roughness elements was an effective approach to optimize the performances of the devices. The experimental results exhibited entirely different flow patterns for ethanol compared to water, which suggests the dominant effect of the surface tension on hydrodynamic cavitation in microfluidic channels.