This study's goal was to investigate the long-term association between cancer risk and depression symptom trajectories, highlighting the need for dynamic evaluation of depressive symptoms across time.Data from 42,911 participants were drawn from two population-based cohorts: the Health and Retirement Study (HRS) from US and the English Longitudinal Study of Ageing (ELSA). The study period covered HRS Rounds 4-12 (1998-2014) and ELSA Rounds 1-9 (2002-2018), with the first six years as the exposure period and the following ten years as the follow-up. The assessment of depressive symptoms was conducted employing the 8-item CES-D scale, with trajectories constructed over repeated assessments. Cancer diagnoses were determined based on self-reported physician confirmations. Cox regression models were used to compute the risk ratios (HR) and 95% confidence intervals (CI), taking into consideration variables linked to health and demographics.Using those with consistently low depressive symptoms as a reference standard, other depressive symptom trajectories were linked to an elevated cancer risk. Patients with symptoms that fluctuate were at the highest risk (HR = 1.79, 95% CI: 1.70-1.90), followed by those with consistently high symptoms and increasing symptoms (HR = 1.46, 95% CI: 1.39-1.50; HR = 1.21, 95% CI: 1.18-1.25, respectively). However, no significant association was found for the decreasing symptom trajectory (HR = 0.95, 95% CI: 0.35-1.21). The total depressive symptom trajectory was a slightly stronger risk factor for cancer than the somatic and cognitive-emotional components.The results support the idea that depressive symptoms are a significant risk factor for the onset of cancer. The fluctuating symptom trajectory exhibited the highest risk, underscoring the importance of considering temporal variations in depressive symptoms for cancer prevention and intervention. Integrating mental health assessments into cancer care may enhance early risk identification and improve patient outcomes.This study is a retrospective analysis and was not registered.© 2025. The Author(s).