Almost every major city’s skyline is known for high-rise iconic buildings with some level of curtain wall system (CWS) installed. Although complex, a CWS can be designed for energy efficiency by integrating insulated spandrel components in space-constrained areas, such as slabs/plenums. The main aim of this study was to experimentally examine the thermal performance of an optimized curtain wall spandrel system integrated with vacuum insulation panel (VIP) as spandrel insulation. The study is based on robust experimental evaluations, augmented with appropriate numerical computations. The main study is constituted of six parts: (1) evaluation of VIP specifications and thermal properties; (2) analysis of VIP spandrel configuration, fabrication, and installation in a test building facility; (3) thermal bridge characterization of VIP spandrels; (4) monitoring and assessment of VIP durability within the spandrel cavities; (5) thermal performance analysis; and (6) assessment of related limitations and challenges, along with some further reflections. In all, 22 VIPs (each of size 600 mm2) were used. The effective thermal conductivity of VIPs ranged from 5.1–5.4 (10−3 W/mK) and the average value for initial inner pressure was approximately 4.3–5.9 mbar. Three VIP spandrel cases were fabricated and tested. The results proved that the Case 3 VIP spandrel configuration (composed of a double-layer VIP) was the most improved alternative for integrating VIPs.