Numerical simulations were used to identify and evaluate optimum electrode configurations and approaches for electrokinetic in situ chemical oxidation (EK-ISCO) remediation of low-permeability sediments. A newly developed groundwater and EK flow and reactive transport numerical model was used to conduct two-dimensional scenario simulations of the coverage of an injected oxidant, permanganate, and the oxidation of a typical organic contaminant (tetrachloroethene, PCE). For linear configurations of vertical electrodes, the spacing of same-polarity electrodes is recommended to be about one-third to one-quarter of the anode–cathode spacing. Greater coverage could also be achieved by locating additional oxidant injection wells at the divergence of the electric field in linear electrode configurations. Horizontal electrodes allowed greater contact between the injected permanganate and PCE and resulted in faster degradation of PCE compared to vertical electrodes. Pulsed oxidant injection, closer electrode spacing, and electric field reversal also resulted in faster EK-ISCO remediation.