Abstract Entropy generation analysis of hybrid nanofluid in a two pass multiport minichannel heat exchanger coupled with a thermoelectric cooler is experimentally investigated. Alumina (Al2O3, 50 nm), graphene (5 nm) and the hybrid of these two in equal portions with 0.1% volume concentrations is separately dispersed in to the base fluid and tested. The hydraulic diameter and aspect ratio of the channel are 1.184 mm and 0.689 respectively. The heat flux is varied from 6250 W/m2 to 25,000 W/m2 and the flow regime is considered to be laminar with the Reynolds number varying from 200 to 1000. The results showed an enhancement of 17.32% in cooling capacity and coefficient of performance (COP) with the use of pure graphene–water nanofluid when compared with that of the other tested combinations of nanofluids. Total entropy generation decreased from 0.0361 W/K to 0.0184 W/K with increase in Reynolds number from 200 to 1000 for the maximum applied heat flux of 25,000 W/m2. Similarly an enhancement of 88.62% in the convective heat transfer coefficient and a reduction of 4.7 °C in the device temperature are achieved when pure graphene–water nanofluid is used as the coolant. Among the tested nanofluids, graphene–water nanofluid shows better performance in terms of heat transfer, thermodynamic and exergic analysis.