This research aims to develop an innovation-based virtual flipped learning system in a ubiquitous learning environment to enhance twenty-first-century learning skills in information, media, and technology of learners in higher education. The study employed a design-based research method to study the needs and user experiences of students and teachers. The system consists of three components: (1) a flipped classroom, (2) a virtual learning system and (3) a ubiquitous learning environment and involved five steps: (1) preparing learners, (2) setting learning objectives, (3) self-studying online content, (4) meeting with teachers and classmates to expand knowledge and (5) assessing results. The participants were 97 undergraduate students. This study found that students had twenty-first-century learning skills in information, media, and technology literacies after studying were significantly higher at the highest level in every skill. The average scores of the test before the study, during the study and after the study had heightened attitude levels and information, media, and technology literacies with statistical significance at the 0.05 level. The results of the test after the study had the highest average scores, followed by those from and before the study. This indicates that the developed innovation can improve the overall attitude and information, media, and technology literacies of learners.