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Background: Support for health‐related quality of life (HRQOL) is an essential part of cancer care in the final stages of life, yet empirical guidance regarding HRQOL and symptom trajectories is lacking. Aim: To assess the change in HRQOL and symptom burden in the last year of life in patients with advanced cancer and its association with health care–related factors, cancer‐specific treatment, and comorbidity. Methods: A prospective, multicenter, observational study in patients with advanced cancer (eQuiPe). Three monthly questionnaires included European Organization for Research and Treatment of Cancer Quality of Life‐C30 and reported continuity of care. Multivariable mixed‐effects analysis was used to assess the association between HRQOL and health care–related factors. Results: A total of 762 deceased patients were included with a mean age of 66 (SD, 10) years and 52% were male. The most common primary tumors were lung (29%), colorectal (20%), and breast cancer (13%). Mean overall HRQOL decreased in the last 9 months of life, with the greatest decrease in the last 3 months (β –16.2). Fatigue, pain, appetite loss, dyspnea, constipation, and nausea worsened significantly in the last year of life. Multimorbidity (β –7.5) and a better reported continuity of care (β 0.7) were both significantly associated with the trajectory of HRQOL. Conclusion: Mean overall HRQOL begins to decline 9 months before death, highlighting the need for early identification and (re)assessment of different symptoms as aspects of HRQOL follow different trajectories. Multimorbidity and reported continuity of care may be associated with the trajectory of HRQOL. Longitudinal results from the eQuiPe study show that the mean health‐related quality of life begins to decline 9 months before death in patients with advanced cancer. Higher perceived continuity with care is associated with an attenuated decline in health‐related quality of life. [ABSTRACT FROM AUTHOR]