This study aspired to determine what domain of 21st Century Core Skills of Students significantly influences the students learning outcomes in Mathematics. The quantitative non-experimental design utilizing causal-effect was used in the study. The respondents of the study were 249 grade 10 students at selected schools in Tagum City of S.Y. 2018-2019. Mean, Pearson-r and Regression Analysis were used in interpreting the data gathered. Findings were, 21st century core skills of students in Mathematics significantly influences to their learning outcomes and three out of four domain of 21st Century Core Skills significantly influences to their learning outcomes. Findings also revealed that the level of 21st century core skills of students in Mathematics was high, the level of students learning outcomes in Mathematics was developing and there was a significant relationship between the 21st Century Core Skills of students in Mathematics. Based on the findings, it would serve as an eye opener to the DepEd as well as to the school and other national organizations in giving more importance on interventions as to fuse the 21st century core skills of the students in Mathematics for a successful and effective in increasing the learning outcomes of the students.