Hyperthermia has been in use for many years, as a potential alternative modality for cancer treatment. In this paper, an experimental investigation of microwave-assisted thermal heating (MWATH) of tissue phantom using a domestic microwave oven has been reported. Computer simulations using finite element method-based tools were also carried out to support the experimental observations and probe insight into the thermal transport aspects deep within the tissue phantom. A good agreement between predicted and measured temperature was achieved. Furthermore, experiments were conducted to investigate the efficacy of dielectric nanoparticles, namely, alumina (Al2O3) and titanium oxide (TiO2) during the MWATH of nanoparticle-infused tumor phantoms. A deep-seated tumor injected with nanoparticle solution was specifically mimicked in the experiments. Interesting results were obtained in terms of spatiotemporal thermal history of the nanoparticle-infused tissue phantoms. An elevation in the temperature distribution was achieved in the vicinity of the targeted zone due to the presence of nanoparticles, and the spatial distribution of temperature was grossly morphed. We conclusively show, using experiments and simulations that unlike other nanoparticle-mediated hyperthermia techniques, direct injection of the nanoparticles within the tumor leads to enhanced heat generation in the neighboring healthy tissues. The inhomogeneity of the hyperthermia event is evident from the local occurrence of hot spots and cold spots, respectively. The present findings may have far-reaching implications as a framework in predicting temperature distributions during microwave ablation (MWA).