Cortical cerebral metabolic rate of oxygen (CMRO2) could conventionally be measured by combining laser Doppler flowmetry and multispectral reflectance imaging across multiple trials of stimulation, which compromises the real-time capacity. Monitoring transient change of CMRO2 has been challenging. In this Letter, imaging photoplethysmography (iPPG) and laser speckle contrast imaging were combined into a multi-modal optical imaging system for single-trial estimation of CMRO2. In a physiologically stable experiment, the iPPG-based method showed a less than 4% variance in comparison with the conventional method over 20 trials, and its temporal stability could be comparable to that by conventional method over 6 trials. While the oxygen supply was decreased deliberately, the new method was able to detect the transient changes of CMRO2 in real time, which could not be revealed by the conventional method.