Particulate matter (PM) inhaled into human lungs causes oxidative stress and adverse health effects through antioxidant depletion (oxidative potential, OP). However, there is limited knowledge regarding the association between the lung-deposited dose (LDD) of PM and OP in extrathoracic (ET), tracheobronchial (TB), and pulmonary (P) regions of human lungs. Dithiothreitol (DTT) and ascorbic acid (AA) assays were employed to measure the OP of PM size fractions to investigate OP distribution in human lungs and identify the chemical drivers. Quasi-ultrafine particles (quasi-UFP, ≤0.49 μm) exhibited high OP deposition in the TB and P regions, while coarse particles (CP, ≥3.0 μm) dominated in the ET region. A plot of extrinsic (per air volume) and intrinsic (per PM mass) OP versus LDD revealed that the OP for fine and coarse particles was greatest in the ET region, whereas the OP of quasi-UFP was greatest in alveoli. The study also demonstrated that extrinsic OP and PM doses are not strongly related. The decline in OP with increasing PM dose reveals the need for further investigation of the antagonistic effects of the chemical compositions. Overall, the results presented herein help address the gap in knowledge regarding the association between the OP and LDD of ambient particles in specific regions of human lungs.