The purpose of this study was to examine faculty members' pedagogical competencies in developing 21stcentury skills at selected universities in Amhara region, Ethiopia. It also sought to analyze faculty members‘ conceptions of the pedagogy of 21st century skills, the current status of pedagogical competencies, and the challenges that impede and opportunities that facilitate in developing 21st century skills at selected universities. To achieve this purpose, an explanatory sequential mixed methods design was employed. Quantitative data were collected from faculty members (n = 322) and students (n = 327) through stratified-based, proportional, randomly selected faculty members and senior undergraduate students. Quantitative data gathering was done using a questionnaire. Qualitative data was collected from 10 purposively selected participants. The qualitative data gathering was using semi-structured interviews and classroom observations from three classrooms. The data were analyzed quantitatively using a one-sample t-test, an ANOVA, an independent sample t-test and descriptive statistical techniques (frequency and percentage). The qualitative data were analyzed thematically using description and narration. The results revealed that participants had a limited understanding or unsatisfactory conception of 21stcentury skills. To be specific, their conceptions were not in line with the ideas and positions of scholars in the field or the global and local policy imperatives. The result also showed those faculty members‘ pedagogical practice in developing such 21st century skills as critical thinking, problem solving, creativity, innovation, collaboration, communication, and information and communication technology was inadequate. There was no significant difference in competencies among the faculties from the three generation universities. However, it was noted that there were significant differences between the competence of faculties in the natural and social science streams in favor of faculty members of natural science. The study also revealed that faculty members faced challenges associated with their knowledge gaps and assessment techniques for 21st century skills. Moreover, insufficient in-service professional development practices, inadequate involvement in curriculum development, inadequate autonomy given to them, and experiencing emerging problems deterred faculty members competencies. A lack of interest and job satisfaction, as well as a shortage of innovative teaching materials and technology-oriented infrastructure, was impeding faculty members' competence in developing 21st century skills. On the other hand, the study explored some potential opportunities for faculty members that are helpful to improve their professional competence. The findings of this study have important implications for faculty members and universities to have empirical evidence about conception, competencies, and challenges that related to practicing the 21st century competence.