Teachers' goal orientations and their adaptation to the 21st century determine many questions in teacher training and professional development. One of these aspects is entrepreneurship, such that the achievement goal orientations and 21st century skills of pre-service teachers have a positive role in entrepreneurship. The present study aimed to investigate the predictive role of the achievement goal orientations and 21st century skills of pre-service teachers in relation to entrepreneurship. To this end, a correlational design was conducted to analyze relationships between variables. The sample in the current study consisted of 282 pre-service teachers studying at a Faculty of Education in Anatolia Province, Turkey. The instruments were the Achievement Goal Orientations Scale, 21st Century Learning Skills Acquisition Scale, and The Scale of Entrepreneurship of College Students. The data obtained from these scales were analyzed using structural equation modeling. The results showed that the structural model of the relationships between achievement goal orientations, 21st century skills, and entrepreneurship had an adequate goodness of fit, so that most of the achievement goal orientations and 21st century skills of pre-service teachers predicted either directly or indirectly their entrepreneurship skills. The conclusion was that entrepreneurial education activities related to teacher entrepreneurship can be planned by considering 21st century skills and achievement goal orientations in teacher education.