This paper discusses the performance of nanofluids in a PV Thermal-driven Organic Rankine Cycle (ORC) with cooling capabilities. This study was intended to investigate the enhancement effect and characteristics of nanofluids; Al2O3, CuO, Fe3O4 and SiO2 on the performance the hybrid system composed of PV Thermal, ORC and cooling coil. The quaternary refrigerant mixture used in the ORC cycle to enhance the ORC efficiency is an environmentally sound refrigerant mixture composed of R152a, R245fa, R125, and R1234fy. It was shown that the enhancement of the efficiency of the hybrid system in question is significantly dependent upon not only the solar radiation but also the nanofluids concentration and the type of nanofluid as well as the fluid temperature driving the ORC. A higher hybrid system efficiency has been overserved with nanofluid CuO. Moreover, it has been also shown that on the average, the hybrid system efficiency was higher 17% with nanofluid CuO compared to water as the heat transfer fluid. In addition, it was also observed that the higher cooling effect produced is significantly increased with the use of the nanofluid CuO compared to the other nanofluids under investigation and water as heat transfer fluid. The results observed in this paper on ORC efficiency and PV solar panel efficiency are comparable to what has been published in the literature.