Background: COVID-19 represents a threat both for the physical and psychological health of oncological patients experiencing heightened distress levels to which the fear of the virus is also added. Moreover, fear of COVID-19 could lead oncological patients to experience feelings of hopelessness related to their medical care. Patient-centered communication may act as a buffer against the aforementioned variables. This study aimed to test the role of doctor–patient communication in the relationship between fear of COVID-19 and hopelessness. Methods: During the COVID-19 pandemic, a sample of 90 oncological outpatients was recruited (40 males (44.4%) and 50 females (55.6%), mean age = 66.08 (SD = 12.12)). A structured interview was developed and used during the pandemic to measure the patients’ perceived (A) fear of COVID-19, and (B) feelings of hopelessness, and (C) physicians’ use of empathetic and (D) clear language during the consultation. A multiple mediation model was tested, and the effects between males and females were also compared. Results: Empathetic and clear doctor–patient communication buffered the adverse effect of the fear of COVID-19 on hopelessness through a full-mediation model. The effects did not differ between males and females in the overall model but its indirect effects. Discussions: Patient-centered communication using empathy and clear language can buffer the adverse effect of the fear of COVID-19 and protect oncological patients from hopelessness during the pandemic. These findings might help to improve clinical oncological practice.