The exergy, entropy, and entransy analysis for a dual-loop organic Rankine cycle (DORC) using a mixture of working fluids have been investigated in this study. A high-temperature (HT) loop was used to recover waste heat from internal combustion engine in 350 °C, and a low-temperature loop (LT) was used to absorb residual heat of engine exhaust gas and HT loop working fluids. Hexane/toluene, cyclopentane/toluene, and R123/toluene were selected as working fluid mixtures for HT loop, while R245fa/pentane was chosen for LT loop. Results indicated that the variation of entropy generation rate, entransy loss, entransy efficiency, and exergy loss are insensitive to the working fluids. The entransy loss rate and system net power output present the same variation trends, whereas a reverse trend for entropy generation rate and entransy efficiency, while the exergy analysis proved to be only utilized under fixed stream conditions. The results also showed that hexane/toluene is the preferred mixture fluid for DORC.