Background: The safety and restriction regulations implemented to contain the COVID-19 pandemic significantly impacted people’s quality of life compromising the perception of dignity. Preserving dignity for end-of-life patients remains a paramount objective in palliative care. This study aimed to compare dignity levels in terminal cancer patients between pre- and during-pandemic periods. Methods: Dignity was assessed by the Italian version of the Patient Dignity Inventory (PDI-IT) in both pre- and during-pandemic groups of terminal cancer inpatients (hospitalized or admitted in hospice). The 2 groups were compared using non-parametric tests and a multivariate logistic regression analysis to estimate the association of the different dimensions of dignity with COVID-19 period, adjusting for other confounders. The study involved 2 groups of end-of-life cancer patients with a Karnofsky Performance Status (KPS) index less than 50. The first group included 506 patients before COVID-19, and the second group consisted of 156 patients enrolled during pandemic. Results: Existential Distress, Loss of Purpose and Meaning, Physical Symptoms and Dependency, Social Support PDI subscales and PDI Total score were higher in the during-pandemic group. The multivariate regression model partially supported the previous results as Loss of Purpose and Meaning, Social Support, and Existential Distress PDI subscales were associated with during-pandemic period, whereas PDI Physical Symptoms and Dependency and PDI Psychological Distress were not. Conclusion: Social isolation and other restrictions put in place to contain the COVID-19 pandemic may have had a negative impact on the perception of dignity in cancer patients at the end of life.