Empathy remains a widely discussed topic within medical education research. Studies on empathy changes among medical students are not univocal: empathy may decline, remain stable or increase. A largely unexplored research question regards inter-individual variability in empathy change, namely if different longitudinal trajectories of empathy exist. Evidence on the association of empathy trajectories with personality and motives for studying medicine is also scarce. Here, latent growth modeling examined empathy (measured with the Jefferson Scale of Empathy) among 201 medical students (Mage = 20.74, 57% females) across three assessments: at entry year (Year 1) and during the first two clinical years (Years 4 and 5). Associations between empathy trajectories, personality in Year 1 and motives for studying medicine in Years 4 and 5 were tested. We identified two empathy trajectory groups: lower and decreasing (n = 59; 29%) and higher and stable (n = 142; 71%). Regression analyses indicated that higher openness in Year 1 was associated with an increased probability of higher and stable group membership (controlling for motives in Year 1). The effect of openness disappeared controlling for motives in Years 4 and 5 while caring for patients (in Years 4 and 5) and altruism (in Year 4) were positively associated with an increased probability of higher and stable group membership. In sum, we observed that empathy remains stable in most medical students and declines in fewer; openness and patients-oriented motives for studying medicine are associated with higher and stable empathy. Encouraging medical students' patients-oriented motives from preclinical throughout clinical years may prevent empathy decline.