The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic led to several needed containment measures that conditioned the onset of depressive, anxiety, and post-traumatic stress symptoms in the population. These symptoms, especially if not diagnosed and treated, can also occur in patients undergoing medical care or surgery, with a high impact on people's lives and causing low adherence to treatment. The study evaluates whether the spread of the coronavirus disease 2019 (COVID-19) worsened the onset of post-surgical distress and symptoms of anxiety and depression in a population undergoing hysterectomy for benign disease during the pandemic era, comparing it with a population with the same characteristics but recruited before COVID-19. The sample was evaluated before surgery (T1), post-operatively (T2), and 3 months after surgery (T3) through a sociodemographic questionnaire and through the HADS (Hospital Anxiety and Depression Scale) to evaluate anxious-depressive symptoms and the PCL-5 (Post-traumatic Stress Disorder Checklist for DSM-5) to assess the onset of post-surgical distress. Patients treated after the COVID-19 pandemic showed a higher depressive symptoms rate compared with those treated before (-value = 0.02); conversely, pre-COVID-19 patients were more prone to develop post-traumatic stress disorder (PTSD) (-value = 0.04). A significant association between the occurrence of PTSD and anxiety-depressive symptoms registered at T2 (-value = 0.007) and T3 (-value < 0.0001) emerged. In the end, the COVID-19 pandemic has exerted a detrimental influence on the mental well-being of the patients under investigation, with a notable exacerbation of their mood disturbances. The findings advocate for the implementation of psychometric and psychodiagnostic assessments to promptly detect high-risk scenarios that could lead to PTSD, compromising treatment compliance and exacerbating the overall outcome, resulting in substantial direct and indirect burdens.