In this paper, the effect of aluminum oxide, Al2O3, nanoparticles’ inclusion into Epocast 50-Al/946 epoxy adhesive at different temperatures, subjected to quasi-static tensile loading, is numerically investigated. The single-lap adhesive joint with two different types of material adherends (composite fiber-reinforced polymer (CFRP) and aluminum (Al) 5083 adherends) and adhesive Epocast 50-A1/hardener 946 were modeled in ABAQUS/CAE. A numerical methodology was proposed to analyze the effect on peel stress and shear stress by adding Al2O3 nanoparticles into the neat adhesive at 25 °C, 50 °C, and 75 °C temperatures at four different locations of the adhesive regions: the interface of the adhesive and aluminum adherend (location A), the middle plane of the adhesive region (location B), the middle longer edge (along the length of the adhesive, location C), and the middle shorter edge (along the width of the adhesive, location D). The results showed that adding nanoparticles into the neat adhesive improves joint strength at room and elevated temperatures. High peel and shear stresses were recorded near both edges of the locations (A, B, C, and D). For location A, adding nanofillers into the adhesive resulted in the reduction in peak peel stress by 1.3% for 25 °C; however, it increased by 2.7% and 10.7% for 50 °C and 75 °C temperatures, respectively. Furthermore, the peak shear stress observed a considerable reduction of 19.6% for 25 °C, but it increased by 7.7% and 8.7% for 50 °C and 75 °C temperatures, respectively, for location A. The same trend was also observed for other locations (i.e., B, C, and D). This signified that adding aluminum oxide nanoparticles in the adhesive resulted in increased stiffness at higher temperatures and increased ductility of the joint, as compared to the joint with neat adhesives at room temperature. Moreover, it was observed that locations A and B were more vulnerable to damage initiation, as the peak of stresses lay near the edges, indicating that the crack initiation would take place close to the edges and propagate towards the center, leading to ultimate failure.