Purpose <p>This study is to investigate the longitudinal trajectories and predictors of the fatigue-pain-sleep disturbance symptom cluster in patients with lung cancer during chemotherapy.</p> Methods <p>Convenience sampling was used to select 230 patients. Fatigue-pain-sleep disturbance symptom cluster assessments were conducted before the first chemotherapy cycle and on the last day of the first, third, and sixth chemotherapy cycles. Psychological resilience, social support, and clinical blood indices were collected pre-first chemotherapy cycle. The latent class growth model was used to analyze the trajectory of symptom cluster, and multivariate logistic regression analysis was conducted to identify predictors of distinct trajectories.</p> Results <p>The results showed that the fatigue-pain-sleep disturbance symptom cluster included three trajectories: high symptom burden increased group, moderate symptom burden persistent group, and low symptom burden persistent group. The higher the nutritional risk, interleukin-1β (IL-1β), and the lower the self-care ability, social support, albumin-to-globulin ratio (AGR), and lymphocyte-to-monocyte ratio (LMR) were the predictors of the high symptom burden increased group. The higher the IL-1β and the lower the AGR were the predictors of the moderate symptom burden persistent group.</p> Conclusion <p>The trajectory of the fatigue-pain-sleep disturbance symptom cluster in patients with lung cancer undergoing chemotherapy showed heterogeneity. Regular symptom assessments are essential, and timely, targeted interventions should be implemented for patients with identified risk factors to mitigate the burden of moderate to high level symptoms experienced during chemotherapy cycles.</p>