BackgroundWith the demand for more effective and engaging teaching strategies in higher education, there is an imperative to blend traditional and innovative methods to optimize student learning outcomes. To address this educational need, this study sets out to design and evaluate a hybrid learning approach that integrates a flipped classroom based on working process systematization (termed “W + flipped classroom”) teaching design with blended online and offline methods based on the BOPPPS (bridge-in, objective/outcome, preassessment, participatory learning, post assessment, summary, termed “B + BOPPPS”) teaching model and explore its application effects in the field of biological separation engineering.MethodsThe undergraduate class of 2020 majoring in biomedical engineering from Huanghuai University was designated the control group (n = 74), while the undergraduate class of 2021 was chosen as the experimental group (n = 79). The control group received traditional teaching methods. The experimental group adopted the integrated “W + flipped classroom” and B + BOPPPS teaching models. After the conclusion of the teaching period, comparisons were made between the two groups in terms of course objective achievement, academic performance, and critical thinking skills. A survey was distributed to assess learning effectiveness. Semistructured interviews were conducted with teachers and students from the experimental group to evaluate teaching effectiveness.ResultsThe integrated “W + flipped classroom” and B + BOPPPS teaching models significantly improved the academic performance and critical thinking skills of the experimental group. The teaching evaluation revealed high levels of acceptance among both teachers and students, along with improved satisfaction with the teaching methodology.ConclusionThe integration of the “W + flipped classroom” teaching design with the “B + BOPPPS” teaching model provides a scientific foundation for future teaching reforms. This study serves as a valuable reference for implementing the OBE philosophy, enhancing learning outcomes, achieving engineering education accreditation, and cultivating high-quality applied talents in the field of bioengineering at applied universities.