A novel integrated approach for chemofacies characterization of organic-rich mudrocks was developed using principal components analysis of 25 elements from core-based energy-dispersive x-ray fluorescence (ED-XRF) measurements and k-means clustering. Using this approach, three chemofacies were identified that capture the spread of the geochemical data sets (∼5000 ED-XRF measurements from three cores) of the organic-rich Cline Shale in the Midland Basin: (1) oxic-suboxic detrital-enriched argillaceous mudrocks, (2) anoxic siliceous mudrocks, and (3) oxic-suboxic intrabasinal carbonates. Chemofacies defined by the covariances of elemental concentrations can be correlated to depositional environments and primary grain assemblages in a predictable way, which has significant implications for the evolution of bulk rock properties, such as total organic carbon (TOC), rock mechanical property, porosity, and permeability. The stratigraphically thin anoxic siliceous mudrocks, which are also characterized by the highest TOC concentrations, moderate to high brittleness, and the highest porosity and permeability, are the “sweet spot” for shale oil production in the Cline Shale. Elevated TOC values of the anoxic siliceous mudrocks are most likely caused by anoxic benthic conditions. This integrated approach for chemofacies characterization of mudrocks is an important step to fully use all the geochemical data obtained through high-resolution ED-XRF analyses and provide an economic, efficient, and nondestructive method to study core.