Human patient simulation (HPS) is becoming a popular teaching method in nursing education globally and is believed to enhance both knowledge and critical thinking. Objective: While there is evidence that HPS improves knowledge, there is no objective nursing data to support HPS impact on critical thinking. Therefore, we studied knowledge and critical thinking before and after HPS in prelicensure nursing students and attempted to identify the predictors of higher critical thinking scores. Methods: Using a one-group, quasi-experimental, pre-test post-test design, 154 prelicensure nursing students (age 25.7 ± 6.7; gender = 87.7% female) from 3 schools were studied at the same point in their curriculum using a high-fidelity simulation. Pre-and post-HPS assessments of knowledge, critical thinking, and self-efficacy were done as well as assessments for demographics and learning style. Results: There was a mean improvement in knowledge scores of 6.5 points (P b 0.001), showing evidence of learning. However, there was no statistically significant change in the critical thinking scores. A logistic regression with 10 covariates revealed three variables to be predictors of higher critical thinking scores: greater "age" (P = 0.01), baseline "knowledge" (P = 0.04) and a low self-efficacy score ("not at all confident") in "baseline self-efficacy in managing a patient's fluid levels" (P = .05). Conclusion: This study reveals that gains in knowledge with HPS do not equate to changes in critical thinking. It does expose the variables of older age, higher baseline knowledge and low self-efficacy in "managing a patient's fluid levels" as being predictive of higher critical thinking ability. Further study is warranted to determine the effect of repeated or sequential simulations (dosing) and timing after the HPS experience on critical thinking gains.