The time‐domain (TD) mode of electron paramagnetic resonance (EPR) data collection offers a means of estimating the concentration of a paramagnetic probe and the oxygen‐dependent linewidth (LW) to generate pO₂ maps with minimal errors. A methodology for noninvasive pO₂ imaging based on the application of TD‐EPR using oxygen‐induced LW broadening of a triarylmethyl (TAM)‐based radical is presented. The decay of pixel intensities in an image is used to estimate T, which is inversely proportional to pO₂. Factors affecting T in each pixel are critically analyzed to extract the contribution of dissolved oxygen to EPR line‐broadening. Suitable experimental and image‐processing parameters were obtained to produce pO₂ maps with minimal artifacts. Image artifacts were also minimized with the use of a novel data collection strategy using multiple gradients. Results from a phantom and in vivo imaging of tumor‐bearing mice validated this novel method of noninvasive oximetry. The current imaging protocols achieve a spatial resolution of ∼1.0 mm and a temporal resolution of ∼9 s for 2D pO₂ mapping, with a reliable oxygen resolution of ∼1 mmHg (0.12% oxygen in gas phase). This work demonstrates that in vivo oximetry can be performed with good sensitivity, accuracy, and high spatial and temporal resolution. Magn Reson Med, 2006. Published 2006 Wiley‐Liss, Inc.