Microchannels are widely used for heat transfer enhancement. The pressure characteristics are one of the most important factors affecting the heat transfer performance, and the pressure regulation may also control the heat transfer precisely in turn. As a common flow pattern of two-phase flow, slug flow has obvious advantages for heat and mass transfer, like steady flow rate and large interface area etc. Due to the interface stress and the velocity difference between the continuous phase and the dispersed phase, pressure fluctuations occur in both the flowing direction and the cross section. In oil and natural gas industries, pressure fluctuations of slug flow can be used for the slug size and velocity measurement, and also to analyze the principle of slug generation. However, when it comes to micro scale, pressure fluctuations of slug flow in microchannels is difficult to measure, not only due to the pressure difference within a low pressure range (10 to 103 Pa), but also because of the small size, for which conventional pressure sensors cannot be utilized. In this paper, a numerical method is adopted for the liquid-liquid slug flow (butanol/water) pressure prediction in a cross-junction square microchannel. To begin with, the validation of the numerical method is carried out by comparing the slug size with experiments under the same working conditions. Then, both pressure fluctuations in the flow direction and in the cross section are investigated. With a transient flow model, pressure fluctuations in the cross section at different flowing time are observed. Finally, effects of the dispersed phase (butanol) injection velocity on pressure fluctuations are performed. This work can be used for further study of the slug generation in microchannels.