College presents a unique environment for exploring, defining, and refining key developmental assets, like one’s senses of identity and self-direction. Although rich with opportunities for self-discovery, college is also rich with opportunities for risk: the transition to and through college is stressful, often associated with the onset or exacerbation of mental illness. This underscores the need to better understand how the college transition, and the developmental processes often occurring within it, are related to well-being. This study followed 579 students from freshman to senior year of college to examine how derailment, or difficulties reconciling perceived identity change, relates to downstream depressive symptoms. There was insufficient evidence to suggest that derailment in freshman year meaningfully predicted levels of depressive symptoms in senior year. Most notably, however, trait self-reflection in freshman year moderated this association, such that derailment was a risk factor for later depression among those with the lowest tendencies toward self-reflection. In the first observation of its kind, univariate latent growth curve modeling suggested that derailment tended to increase linearly from freshman to senior year, and depressive symptoms were characterized by a significant uptick in distress across the first semester of college that appeared to persist through the end of senior year. Exploratory qualitative analyses, aided by a machine learning tool for text analysis known as Latent Dirichlet Allocation, were also conducted to provide the field with its first topographical understanding of derailment. This led to the discovery of five themes associated with students’ derailment experiences that may have implications for the way derailment interfaces with mental health: Insight into Personal Changes (e.g., progression, regression, and stability), Overcoming Challenges (e.g., growing as a result of hardship), Evaluating Clarity of Direction (e.g., optimism, confidence, certainty, or anxiety surrounding one’s path or lack thereof), Contending with Major Turbulence (e.g., mental illness, death, poverty), and The Path (e.g., objective reports of changes in career trajectory). With derailment representing a novel psychological construct that synthesizes developmental, social, and clinical fields, these findings can inform interventions aimed at promoting healthy transitions to adulthood.