It is important to raise enterprising individuals in STEM fields so that countries have individuals, who will play a role in global competition, and this is possible with effective STEM education. This research aims to reveal the impact of STEM activities, which were designed using the 6E learning byDeSIGN™ model, in terms of developing middle school students' entrepreneurial skills, STEM attitude, and career interests. The STEM activities were applied for seven weeks / twenty-eight hours with 50 (26 female, 24 male) students in the research which was carried out by the mixed-method methodology. Before and after the application, the quantitative data collection tools (STEM Attitude Scale, Interest towards STEM Professions Scale, and Entrepreneurship Scale) were applied and statistically analyzed. The qualitative data were collected by semi-structured interviews and evaluated with content analysis at the end of the application to interpret and support the findings obtained from these quantitative data. As a result of the research, it was concluded that the attitude and interests of the students towards STEM increased, their entrepreneurship skills improved and the effect of 6E teaching strategy was great in these positive developments. Student opinions were also got and discussed for supporting these results.