The temperature glide effect of zeotropic mixtures on ocean thermal energy conversion (OTEC) cycle driven by a narrow temperature difference, which is significantly different from that in conventional low-grade energy technologies, is yet to be thoroughly studied. In this study, the binary zeotropic mixtures-based OTEC cycle is investigated. Comparative analysis of the classical zeotropic ORC and six types of zeotropic ORCs configured with or without series/parallel multi-pressure evaporators and single-/dual-outlet liquid-separated condensers were conducted. The results showed that zeotropic mixtures could be beneficial in ocean thermal energy conversion. Multi-pressure evaporation could significantly reduce the irreversible loss in the heat exchanger, and the series multi-pressure evaporator-based zeotropic ORC (SMZO) performed better than the parallel cycle (PMZO), with 0.09%–0.14% higher thermal efficiency, 2.27%–3.11% higher turbine power output, and 0.89%–1.46% higher exergy efficiency. Liquid-separated condensation could improve the condensation effect by increasing the heat transfer coefficient, and liquid-separated dryness dominant the performance. Dual-outlet liquid-separated condensation could also increase cycle-levelised energy cost. Comparingly, the single-outlet liquid-separated condensation based cycle could reduce the levelised energy cost by 7.93% and 4.81%, respectively.