Introduction/Background: Burnout is a three-dimensional syndrome characterized by exhaustion that appears when the professional is constantly exposed to a stressful work environment, as well as depersonalization and lower personal accomplishment. Professional quality of life at work can be defined as the satisfaction degree that a person feels when being or going to their workplace. Objective: To evaluate burnout and professional quality of life in healthcare professionals working in oncology and palliative care. Material and methods: A cross-sectional, observational, and descriptive study was carried out in a convenience sample of 337 healthcare professionals from a Portuguese Oncology Hospital. The assessment tools were a sociodemographic questionnaire, the Maslach Burnout Inventory (MBI), and the Professional Quality of Life—version 5 (proQOL-5) scales. Statistical analysis was performed using the IBM SPSS® Statistics program (significance level of 95% (p ≤ 0.05)). Results: The majority of professionals were female (84%), with a median age of 41 years. Most professionals work in oncological care services (76.8%), with an average of 40 h a week. There were no statistically significant differences in MBI and ProQOL dimensions between the two groups studied (professionals working in oncology vs. palliative care). In the sample and group of professionals working with palliative patients, it was observed that lower levels of compassion satisfaction were related to higher levels of emotional exhaustion (p < 0.001). On the other hand, higher levels of satisfaction correlated with a greater sense of personal accomplishment (p < 0.001); higher levels of secondary traumatic stress were related to a greater tendency towards emotional exhaustion (p < 0.001) and depersonalization (p = 0.031). Discussion and conclusions: Working in oncology and palliative care may predispose one to the onset of burnout related to contact with distress and suffering. With this study, the authors intend to demonstrate that both scales (MBI and ProQOL) are complementary in the analysis of the prevalence of burnout and professional quality of life, particularly in the context of oncology and palliative care. The risk of compassion fatigue and burnout highlights the need to develop coping strategies to minimize this risk and improve the quality of life and bonding of health professionals.