Background/Objectives: Advanced rectal cancer is one of the most common cancers worldwide and has a significant impact on public health. Because favorable and long-term survival has been achieved with multimodal therapy, patient quality of life is very important. The intention of this study was to assess patients’ quality of life using various functioning and symptom scores from the years 2010 to 2022 and to examine changes over time. Methods: Data on health-related quality of life were collected from rectal cancer patients treated at the University Hospital Erlangen in Germany over a period of 13 years. The EORTC QLQ-C30 questionnaire and the rectal cancer-specific module QLQ-CR38 were completed in this study by a total of 516 patients. The questionnaires were collected before, during and at annual follow-up visits after treatment. Statistical significance was defined as p-values < 0.05 as well as a difference of 10 or more percentage points. Results: The deterioration in scores is most pronounced immediately after radiochemotherapy, especially for pain (+19.8 pp), fatigue (+16.1 pp) and diarrhoea (+24.8 pp). One year after the end of therapy, most of the values are again comparable to or better than those of the German general population and only role functioning (−19.8 pp), social functioning (−24.6 pp), diarrhoea (−21.6 pp) and financial difficulties (−16.3 pp) are considerably worse. Some baselines deteriorate clearly over time from 2010 to 2022; these are role functioning (−23.9 pp), social functioning (−17.3 pp), body image (−15.2 pp), fatigue (+13.8 pp) and nausea and vomiting (+10.5 pp). Conclusions: An improvement in therapy in terms of a reduction in side effects and, thus, an improvement in quality of life over time could not be proven. The deterioration in individual scores over time does not appear to be a problem specific to rectal cancer patients, but rather, is associated with social developments or systemic healthcare factors in German society that are not directly related to oncological diseases.