Abstract Purpose Patients with acromegaly oftentimes exhibit a reduced physical and psychological health-related quality of life (HRQoL). Maladaptive coping styles are associated with poor HRQoL in a number of diseases and patients with pituitary adenomas in general exhibit less effective coping styles than healthy controls. This study aimed to assess coping strategies in acromegaly patients in order to explore leverage points for the improvement of HRQoL. Methods In this cross-sectional study, we administered self-report surveys for coping strategies and HRQoL (Short Form SF-36, Freiburg questionnaire on coping with illness, FKV-LIS) in patients with acromegaly. These were set into relation with a variety of health variables. Results About half of the 106 patients (44.3% female) with a mean age of 56.4 ± 1.3 years showed impaired physical and psychological HRQoL on average 11.2 years after the initial diagnosis. Body mass index, age at survey date and concomitant radiotherapy explained 27.8% of the variance of physical HRQoL, while depressive coping added an additional 9.2%. Depressive coping style and trivialization and wishful thinking were pivotal predictors of an impaired psychological HRQoL with a total explained variance of 51.6%, whereas patient health variables did not affect psychological HRQoL. Conclusion Our results show that maladaptive coping styles have a substantial negative impact on psychological HRQoL in patients with acromegaly, whereas physical HRQoL is influenced to a lesser extent. Specialized training programs aimed at improving coping strategies could reduce long-term disease burden and increase HRQoL in the affected patients.