.Significance: Multi-exposure laser speckle contrast imaging (MELSCI) estimates microcirculatory blood perfusion more accurately than single-exposure LSCI. However, the technique has been hampered by technical limitations due to massive data throughput requirements and nonlinear inverse search algorithms, limiting it to an offline technique where data must be postprocessed.Aim: To present an MELSCI system capable of continuous acquisition and processing of MELSCI data, enabling real-time video-rate perfusion imaging with high accuracy.Approach: The MELSCI algorithm was implemented in programmable hardware (field programmable gate array) closely interfaced to a high-speed CMOS sensor for real-time calculation. Perfusion images were estimated in real-time from the MELSCI data using an artificial neural network trained on simulated data. The MELSCI perfusion was compared to two existing single-exposure metrics both quantitatively in a controlled phantom experiment and qualitatively in vivo.Results: The MELSCI perfusion shows higher signal dynamics compared to both single-exposure metrics, both spatially and temporally where heartbeat-related variations are resolved in much greater detail. The MELSCI perfusion is less susceptible to measurement noise and is more linear with respect to laser Doppler perfusion in the phantom experiment ().Conclusions: The presented MELSCI system allows for real-time acquisition and calculation of high-quality perfusion at 15.6 frames per second.