The U.S. Nuclear Regulatory Commission (NRC) is proposing a new rulemaking on emergency core system/loss-of-coolant accident (LOCA) performance analysis. In the proposed rulemaking, designated as 10 CFR 50.46c, the NRC puts forward an equivalent cladding oxidation criterion as a function of cladding pretransient hydrogen content. The proposed rulemaking imposes more restrictive and burnup-dependent cladding embrittlement criteria; consequently, more fuel rods need to be analyzed under LOCA conditions to maintain the safety margin, in contrast to the current practice for which only one hot rod needs to be analyzed. New multiphysics analysis methods are required to provide a thorough characterization of the reactor core in order to identify the locations of the limiting rods and quantify safety margins under LOCA conditions. The U.S. Department of Energy’s Light Water Reactor Sustainability Program has initiated a project to develop multiphysics analytical capabilities, called LOTUS, to support the industry in the transition to the proposed rule. An approach to uncertainty quantification and sensitivity analysis with LOTUS was developed. A typical four-loop pressurized water reactor plant model was developed for RELAP5-3D simulations with inputs generated from core design and fuel performance analyses, and uncertainty quantification and sensitivity analysis were performed with 17 uncertain input parameters. The maximum equivalent cladding reacted ratio and peak clad temperature ratio were selected as the figures of merit (FOMs). Pearson, Spearman, partial correlation coefficients, and Sobol indices were considered for all of the FOMs in the sensitivity analysis.