Heat transfer study from the heated square cylinder at a different orientation angle to the stream of nanofluids has been investigated numerically. CuO-based nanofluids were used to elucidate the significant effect of parameters: Reynolds number (1–40), nanoparticle volume fraction (0.00–0.05), the diameter of the NPs (30–100 mn) and the orientation of square cylinder (0–90°). The numerical results were expressed in terms of isotherm contours and average Nusselt number to explain the effect of relevant parameters. Over the range of conditions, the separation of the boundary layers of nanofluids increased with the size of the NPs as compared to pure water. NPs volume fraction and its size had a significant effect on heat transfer rate. The square cylinder of orientation angle (45°) gained a more efficient heat transfer cylinder than other orientation angles. Finally, the correlations were developed for the average Nusselt number in terms of the relevant parameters for 45° orientation of the cylinder for new applications.