Entrepreneurship skills are part of the essential skills in facing 21st-century challenges and demands. Therefore, this study aims to analyze the extent to which the empowerment of the creative entrepreneurship learning-based discovery skills (CEL-BaDiS Up) learning model can improve university students' science-based entrepreneurship (SciPreneur) skills on the topic of food biotechnology. This quasi-experimental research study employed a pretest-posttest control group design at a public university in Surakarta, Indonesia, in the 2020/2021 academic year, in which one class was as an experimental class using the CEL-BaDiS Up model, while the other class was an existing class utilizing a project-based learning (PjBL) model. Data were obtained through test instruments in the form of a performance assessment to measure SciPreneur skills, which had gone through expert validation, encompassing validation from education and evaluation experts, biotechnology experts, and certified natural science lecturers, and empirical validation tests had also been carried out. The results revealed that the effectiveness test score utilizing SEM from PLS software showed the effect of CEL-BaDiS Up (X1) on the SciPreneur skills (Y) variable of 2.105 > T-table (1.976). In addition, the original sample estimate value exhibited a positive value of 0.199, signifying the direction of the relationship between the CEL-BaDiS Up (X1) variable and the SciPreneur Skills (Y) variable was positive. Based on this study's results, it could be denoted that SciPreneur skills in the aspects of critical thinking skills, problem-solving skills, communication skills, collaborative skills, observational skills, and creativity and innovation could be improved effectively through the CEL-BaDiS Up model activities.