An increasing number of Earth-observing satellite sensors are being launched to meet the insatiable demand for timely and accurate data to aid the understanding of the Earth’s complex systems and to monitor significant changes to them. To make full use of the data from these sensors, it is mandatory to bring them to a common radiometric scale through a cross-calibration approach. Commonly, cross-calibration data were acquired from selected pseudo-invariant calibration sites (PICS), located primarily throughout the Saharan desert in North Africa, determined to be temporally, spatially, and spectrally stable. The major limitation to this approach is that long periods of time are required to assemble sufficiently sampled cloud-free cross-calibration datasets. Recently, Shrestha et al. identified extended, cluster-based sites potentially suitable for PICS-based cross-calibration and estimated representative hyperspectral profiles for them. This work investigates the performance of extended pseudo-invariant calibration sites (EPICS) in cross-calibration for one of Shrestha’s clusters, Cluster 13, by comparing its results to those obtained from a traditional PICS-based cross-calibration. The use of EPICS clusters can significantly increase the number of cross-calibration opportunities within a much shorter time period. The cross-calibration gain ratio estimated using a cluster-based approach had a similar accuracy to the cross-calibration gain derived from region of interest (ROI)-based approaches. The cluster-based cross-calibration gain ratio is consistent within approximately 2% of the ROI-based cross-calibration gain ratio for all bands except for the coastal and shortwave-infrared (SWIR) 2 bands. These results show that image data from any region within Cluster 13 can be used for sensor cross-calibration.