Abstract Los Alamos National Laboratory (LANL) designs and utilizes impulsively loaded pressure vessels for the confinement of experimental configurations involving explosives. For physics experiments with hazardous materials, a two-barrier containment system is needed, where an impulsively (or, explosively) loaded pressure vessel is assembled as an inner confinement vessel, inside an outer containment vessel (subject to quasi-static load in the event of confinement vessel breach). Design of the inner and outer vessels and support structure must account for any directional loads imparted by the blast loading on the inner vessel. Typically there is a shock-attenuating assembly between the inner confinement and outer containment pressure barriers, which serves to mitigate any dynamic load transfer from inner to outer vessel. Depending on the shock-attenuating approach, numerical predictions of these reaction loads can come with high levels of uncertainty due to model sensitivities. Present work here focuses on the numerical predictions and measurements of the reaction loads due to detonating 30 g of TNT equivalent in the Inner Pressure Confinement Vessel (IPCV) for proton imaging of small-scale shock physics experiments at LANL. Direct reaction load measurements from IPCV testing is presented alongside numerical predictions. Using the experimental measurements from the firing site, we refine the tools and methodology utilized for reaction load predictions and explore the primary model sensitivities which contribute to uncertainties. The numerical tools, modeling methodology, and primary drivers of model uncertainty identified here will improve the capability to model detonation experiments and enable design load calculations of other impulsively loaded pressure vessels with higher accuracy.