The purpose of this study was to examine eighth-grade students' science performance in terms of two test design components, item format, and cognitive domain. The portion of Taiwanese data came from the 2011 administration of the Trends in International Mathematics and Science Study (TIMSS), one of the major international large-scale assessments in science. The item difficulty analysis was initially applied to show the proportion of correct items. A regression-based cumulative link mixed modeling (CLMM) approach was further utilized to estimate the impact of item format, cognitive domain, and their interaction on the students' science scores. The results of the proportion-correct statistics showed that constructed-response items were more difficult than multiple-choice items, and that the reasoning cognitive domain items were more difficult compared to the items in the applying and knowing domains. In terms of the CLMM results, students tended to obtain higher scores when answering constructed-response items as well as items in the applying cognitive domain. When the two predictors and the interaction term were included together, the directions and magnitudes of the predictors on student science performance changed substantially. Plausible explanations for the complex nature of the effects of the two test-design predictors on student science performance are discussed. The results provide practical, empirical-based evidence for test developers, teachers, and stakeholders to be aware of the differential function of item format, cognitive domain, and their interaction in students' science performance.