Based on the theory of Synergistic Leadership (Irby et al., 2002), as well as the Framework for 21st Century Learning (P21, 2019) and related research, this research applied mixed methods with questionnaire surveys and interviews to propose the supporting leadership factors for the mastery of core competencies for College English (CE) learners in one of the application-oriented universities (AOUs) in Shanghai, China. The research objectives included: 1) to identify the elements of support systems desirable for supporting the mastery of core competencies for CE learners; 2) to determine the leadership factors expected to support the mastery of core competencies for CE learners in AOUs in Shanghai, China. The quantitative analysis was applied on the data from literature, as well as the questionnaire surveys with 428 learners and 19 instructors, whereas qualitative method analyzed the data from the interviews with one instructional leader and two professors in this AOU. In terms of the educational elements coded from literature, 39 supporting leadership factors were synthesized and proposed, categorized into synergistic leadership factors of stakeholders' perception, leadership behavior, and external forces.