Structural insulated panels, commonly known as SIPs, constitute a panelized building system composed of external facer panels, such as oriented strandboard (OSB) sheets, bonded to a lightweight foam core. As the demand for SIPs increases as an alternative to light-frame construction in residential and light-commercial buildings, so too does the need for proper design requirements to satisfy regulatory agencies and building officials. This paper describes a combined experimental and analytical study whose objective was to investigate the structural behavior of OSB-faced SIPs subject to short-term axial loading. A total of 53 panels with varying types of foam core, thickness, and other construction details were subjected to concentric and eccentric loading. The test results indicated that the strength of SIPs was primarily influenced by the panel slenderness and the type of foam core. Reliability-based design expressions were developed for the ultimate limit state of SIPs subjected to short-duration concentric and eccentric axial loading. The results were also compared to current allowable stress design practices. In addition to presenting important test data for researchers, this paper presents a number of practical design recommendations to improve the performance of SIPs.