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This chapter aims to analyze the effectiveness of problem-based learning (PBL) with Distance E-Learning (DEL) to improve academic achievement and 21st Century Skills (Cs21) of Irbid National University (INU) students in “Operating System” and “Science Education Methods” courses. This study employs a quasi-experimental design of a Non-Equivalent Post-Test Only Control Group Design to two experimental groups and two control groups. A total of 120 students from science and humanity faculties were enrolled in the study. The experimental group students were taught the subject through PBL with DEL while the control group students received the face-to-face (FTF) instruction. Academic achievement was measured using an achievement test, and 21st Century Skills was measured using Cs21 questionnaire. The data were analyzed using quantitative measures, which are mainly ANCOVA and ANOVA. Results of the study revealed that students in PBL with DEL classes had higher mean scores on achievement test and Cs21. Therefore, the PBL with DEL students appeared to be better compared to the FTF students in terms of academic achievement and Cs21. However, PBL with DEL effectively enhances academic achievement for science course students more than humanities course students.

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