Background/Objectives: Quality of life (QoL) is a valuable tool for evaluating treatment outcomes and identifying patients who may benefit from early supportive interventions. This study aimed to determine whether specific QoL results in patients with advanced rectal cancer could identify groups with an unfavourable prognosis in long-term follow-up. Methods: A total of 570 patients with advanced rectal cancer were prospectively assessed, during and up to five years after neoadjuvant radiochemotherapy, using the QLQ-C30 and QLQ-CR38 questionnaires. We analysed 27 functional and symptom-related scores to identify associations with overall survival, once at baseline, three times during therapy, and annually from years one to five post-therapy. Results: Poor quality of life scores were consistently associated with shorter overall survival. The functional scores of physical functioning, role functioning, and global health, as well as the symptom scores of fatigue, dyspnoea, and chemotherapy side effects, were highly significant for overall survival at nearly all time points except for the immediate preoperative assessment. Patients over the age of 64 with lower QoL scores showed a significantly reduced probability of survival in the follow-up period, and patients who reported poor QoL in at least two of the first three questionnaires during the initial phase of treatment showed significantly reduced overall survival. Conclusions: Early and repeated QoL assessments, particularly within the first weeks of therapy, offer critical prognostic value in advanced rectal cancer. Identifying patients with an unfavourable prognosis might allow faster interventions that could improve survival outcomes. Integrating QoL monitoring into routine clinical practice could enhance individualised care and support risk stratification.