In this study, the effects of the STEM activities integrated with socio-scientific issues on students' 21st century skills were investigated. In this research, nested mixed design was used. The study group of this research consisted of 16 middle school students who studied in the seventh grade of a public school in an eastern province of Turkey. Socio-scientific STEM activities were applied to the study group for 24 weeks in the first and second semesters. Students followed the engineering design stages for STEM activities. In the research, 21st Century Skills Scale, Interview Form, Perception of 21st Century Skills Form, Field Notes, and Informal Interview Notes were used as data collection tools. SPSS was used to analyze the quantitative data of the research, and content and descriptive analysis methods were used to analyze the qualitative data. The study results showed that STEM activities integrated with socio-scientific issues had a positive effect on students' 21st century skills. Also, as a result of the examination of the opinions of the students, it was determined that the application developed the "creativity and innovation" skills of the students the most. Furthermore, students' social and intercultural entrepreneurship, self-management, leadership and responsibility, critical thinking, problem solving, communication and cooperation, creativity and innovation skills were enhanced/developed at the end of the study.