Loneliness and depression are significant mental health challenges among college students; however, the intricate relationship between these phenomena remains unclear, particularly in the context of self-compassion. In this comprehensive study, we employ a cross-lagged panel network (CLPN) analysis to investigate the symptom-level association between depression and loneliness while exploring the potential moderating influence of self-compassion. Our sample consisted of 2785 college students, who were categorized into high- and low-self-compassion groups based on scores from the Self-Compassion Scale. Depressive symptoms were assessed using the Patient Health Questionnaire-9, while the UCLA Loneliness Scale-8 measured loneliness expressions. Our findings indicate that self-compassion plays a crucial role in the relationship between depression and loneliness. Specifically, we observed distinctive patterns within the high and low-self-compassion groups. In the low-self-compassion group, “energy” emerged as the most influential symptom, whereas “motor function” exhibited the highest influence in the high-self-compassion group. Furthermore, among individuals with high self-compassion, the pathway from depression to loneliness was characterized by “guilt—being alone when desired,” while the reverse path from loneliness to depression encompassed “left out—feeling sad” and “left out—anhedonia.” Conversely, in the low-self-compassion group, depression and loneliness demonstrated a more intricate mutual triggering relationship, suggesting that self-compassion effectively moderates the association between these variables. This study provides valuable insights into the underlying mechanisms driving the interplay between depression and loneliness, shedding light on the pivotal role of self-compassion in this intricate dynamic.