The purpose of this research is to illustrate the effect of a program based on Technological Pedagogical and Content Knowledge (TPACK) to enhance prospective teachers’ EFL 21st century skills at the faculty of Specific Education. The participants of the study consisted of 30 students divided into two groups: An experimental group of 15 students and the control one of 15students. The groups were randomly chosen from the EFL students at the Faculty of Specific Education, Zagazig University, Egypt. A program based on TPACK was used in teaching the experimental group, while the regular instruction was used in teaching the control one in the second term of the academic year 2022-2023. The study instruments were (a) an EFL 21st century skills checklist which was divided into four parts of EFL 21st century skills with their sub-skills including: critical thinking, creativity, communication and collaboration skills (4Cs), (b) an EFL 21st century test that was designed and validated to be used as a pre-posttest and (c) an observation sheet to observe whether the prospective teachers use the EFL 21st century skills (4Cs) in their teaching or not. Having administered the test and the observation sheet to both groups after the treatment. Data were collected and statistically analyzed. The results of the study revealed that the program based on TPACK had a large effect on developing EFL 21st century skills among prospective teachers of English Language.