Background: Relevant information is a prerequisite for patients to acquire enough knowledge to enable them to be actively involved in shared decision making, to comply with the treatment plan, and to understand what are potential benefits and side-effects of proposed therapy. Aim: The aim of this prospective, longitudinal study was to investigate whether cancer patients’ level of knowledge about their disease and treatment was associated with their health-related quality of life (HRQOL), particularly stress level. Patients and Methods: From October 2017 till September 2018, 41 patients aged 26–69 (median, 42) years referred for curative thyroidectomy were included into the study. EORTC QLQ-INFO25 questionnaire was used to measure level of patients’ knowledge about their disease and treatment, while thyroid-specific HRQOL was measured using Polish version of ThyPRO questionnaire and stress level by COPE Inventory. Assessments were done directly before the surgery (T1), 3 months after (T2), and 6 months after the treatment (T3). Results: The information about the disease (T1: 39.2, T2: 47.6, T3: 52.8; P=.024), information about treatment (T1: 27.2, T2: 42.6, T3: 60.8; P<.001), information about what patients can do to help themselves (T1: 22.6, T2: 39.4, T3: 52.2; P=.037), and satisfaction with the received information (T1: 32.6, T2: 41.0, T3: 49.7; P=.049) increased significantly during the study period. Moreover, the proportion of patients who wished they had received more information decreased from 59.4% at T1 to 22.8% at T3 (P<.001). Almost all of HRQOL domain scores were increasing in the consecutive time points with respect to role-physical (T1: 72.7, T2: 79.2, T3: 80.7; P=.003), role-emotional (T1: 77.6, T2: 82.8, T3: 88.9; P=.001), general health (T1: 52.7, T2: 60.2, T3: 63.4; P<.001), physical functioning (T1: 69.7, T2: 77.8, T3: 79.4; P=.011), social functioning (T1: 82.7, T2: 88.9, T3: 89.4; P=.047), and vitality (T1: 69.3, T2: 72.8, T3: 79.9; P<.001). Based on COPE Inventory, from the relative scores on various coping strategies in each time point, the 5 most common coping strategies adopted were active coping, planning, suppression of competing activities, focus on emotions, and positive reinterpretation and growth. There was significant correlation between EORTC QLQ-INFO25, ThyPRO, and COPE Inventory, in particular study time point (P<.001). Conclusions: Patients’ knowledge increased significantly during the study period, and they reported that they felt better informed and were more satisfied with the information. This significantly influenced improvement of HRQOL and stress reduction. Psychological outcome must be considered as important measurement assessing treatment effect.