Electrokinetic pumps are a novel microfluidic technology being pursued for microscale high performance liquid chromatography (HPLC) and heat transfer applications. These pumps are typically reported to have efficiencies of only a few percent or less. We present an analytical and numerical investigation of the thermodynamic efficiency of electrokinetic pumping, solving the hydrodynamic and fully nonlinear Poisson–Boltzmann equations over a wide range of various dimensionless parameters. The numerical results show that efficiency as high as 15% may be attainable, when using uniform submicron-depth microchannels in substrates with moderately high zeta potentials, as well as using electrolytes with low specific conductivity (we identify practical candidate electrolytes). Simple design rules are given for pump dimensions and working electrolyte, based on dimensionless parameters such as the ratio of Debye layer thickness to channel depth, normalized zeta potential, and operating pressure. We compare our results with existing experimental data and provide practical design examples.