This was an exploratory study to examine whether a specific open inquiry learning framework can be applied in teaching Science courses. The research has employed a true experimental design using qualitative research methods. It aimed to evaluate the 21st century skills acquired and the learning experience of the students exposed in the open inquiry learning framework. It intended to provide teachers with insights on how to properly implement open inquiry learning framework based on the findings of this research. The study was implemented at a state university in Iba, Zambales, Philippines. Respondents were Grade 11 students under Science, Technology, Engineering and Mathematics (STEM) track. The study involved triangulation of data: data were collected from open-ended questionnaires, focused group discussions and observations. NVivo 11 QSR International was used to increase the analysis transparency, accuracy, efficiency, rigour and trustworthiness. The learners were found to have developed the 21st century skills: a) cognitive, b) interpersonal and c) intrapersonal. Upon evaluating students’ 21st century skills, two categories emerged. Students have gained cognitive and interpersonal competencies. Cognitive competencies that were developed involved science process skills, critical thinking, and creativity, while interpersonal competencies include communication and collaborative skills. Three categories emerged to describe the students learning experience during the open inquiry learning framework: sources of difficulties, scaffolds of learning and learning opportunities. Sources of difficulties are absence of prior knowledge and experience, group interaction, students’ attitudes, experimental design and availability of materials. Scaffolds of learning were identified as internet resources, brainstorming and alternative experiment. The learning opportunities revealed in this study are questioning, research, experiments and presentation. The framework has been effective in the development of 21st century skills and learning of students, thus, it should be widely applied in Science instruction.