Design of effective microcooling systems to address the challenges of ever increasing heat flux from microdevices requires deep examination of real-time problems and has been tackled in depth. The most common (and apparently misleading) assumption while designing microcooling systems is that the heat flux generated by the device is uniform, but the reality is far from this. Detailed simulations have been performed by considering nonuniform heat load employing the configurations U, I, and Z for parallel microchannel systems with water and nanofluids as the coolants. An Intel® Core™ i7-4770 3.40 GHz quad core processor has been mimicked using heat load data retrieved from a real microprocessor with nonuniform core activity. This study clearly demonstrates that there is a nonuniform thermal load induced temperature maldistribution along with the already existent flow maldistribution induced temperature maldistribution. The suitable configuration(s) for maximum possible overall heat removal for a hot zone while maximizing the uniformity of cooling have been tabulated. An Eulerian-Lagrangian model of the nanofluids shows that such “smart” coolants not only reduce the hot spot core temperature but also the hot spot core region and thermal slip mechanisms of Brownian diffusion and thermophoresis are at the crux of this. The present work conclusively shows that high flow maldistribution leads to high thermal maldistribution, as the common prevalent notion is no longer valid and existing maldistribution can be effectively utilized to tackle specific hot spot location, making the present study important to the field.