Multiple studies have demonstrated that laser speckle contrast imaging (LSCI) has high potential to be a valuable cerebral blood flow monitoring technique during neurosurgery. However, the quantitative accuracy and sensitivity of LSCI is limited, and highly dependent on the exposure time. An extension to LSCI called multi-exposure speckle imaging (MESI) overcomes these limitations, and was evaluated intraoperatively in patients undergoing brain tumor resection. This clinical study (n = 8) recorded multiple exposure times from the same cortical tissue area spanning 0.5–20 ms, and evaluated images individually as single-exposure LSCI and jointly using the MESI model. This study demonstrated that the MESI estimates provided the broadest flow sensitivity for sampling the flow magnitude in the human brain, closely followed by the shorter exposure times. Conservation of flow analysis on vascular bifurcations was used to validate physiological accuracy, with highly conserved flow estimates (<10%) from both MESI and 1 ms LSCI (n = 14 branches). The MESI model had high goodness-of-fit with proper image calibration and acquisition, and was used to monitor blood flow changes after tissue cautery. Results from this study demonstrate that intraoperative MESI can be performed with high quantitative accuracy and sensitivity for cerebral blood flow monitoring.