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Students’ perceptions of challenges in biology influence performance outcomes, experiences, and persistence in science. Identifying sources of student struggle can assist efforts to support students as they overcome challenges in their undergraduate educations. In this study, we characterized student experiences of struggle by 1) quantifying which external factors relate to perceptions of encountering and overcoming struggle in introductory biology and 2) identifying factors to which students attribute their struggle in biology. We found a significant effect of Course, Instructor, and Incoming Preparation on student struggle, in which students with lower Incoming Preparation were more likely to report struggle and the inability to overcome struggle. We also observed significant differences in performance outcomes between students who did and did not encounter struggle and between students who did and did not overcome their struggle. Using inductive coding, we categorized student responses outlining causes of struggle, and using axial coding, we further categorized these as internally or externally attributed factors. External sources (i.e., Prior Biology, COVID-19, External Resources, Classroom Factors) were more commonly cited as the reason(s) students did or did not struggle. We conclude with recommendations for instructors, highlighting equitable teaching strategies and practices.