The withdrawal of students from Principles of Chemistry courses is a major problem for STEM retention and graduation rates, which are topics of national interest. In order to implement effective intervention methods to reduce withdrawal rates, we must understand the underlying reasons why students withdraw. This paper presents a multimethod study on student withdrawals from Principles of Chemistry from summer 2015 to fall 2018 semester. Eleven students who withdrew were interviewed, and thematic analysis and cluster analysis were used to interpret interview data to understand their reasons for withdrawing. Practical reasons included course structure, student-faculty relationship, student personal factors, chemistry content, and study strategies and academic support. Four themes identified from thematic analysis (hopeless, uncomfortable, demotivated, and overwhelmed) provided deeper insight into the affective emotional factors that contributed to the withdrawals. Cluster analysis revealed natural groupings of student responses and motivations, suggesting that targeted interventions can be developed for different groups. To ensure that our results are comparable to previous studies on course withdrawals, students who withdrew were analyzed according to demographic data. Results revealed that some groups had higher withdrawal rates compared to students who passed the course, which may reflect different levels of academic preparedness and thus an advantage/disadvantage. The analyses presented here will be of value when considering intervention approaches to reduce withdrawals from challenging courses.