Background: Hope is widely considered a subjective phenomenon able to bring beneficial consequences to human health and existence. Maintaining hope amid a life-threatening disease and during palliative care is critical. The study aims to examine the effectiveness of a psychosocial supportive Hope Promotion Program (HPP) in enhancing hope, comfort, and quality of life in Portuguese adult outpatients with advanced and progressive chronic illness. Method: Using a parallel Randomized Control Trial (RCT) with pre-post design, 56 cancer outpatients from two day hospitals. Participants were randomly assigned to either a control group (n = 28) or an intervention group (n = 28). The primary outcome measure was hope. Secondary measures included comfort and quality of life. Participants were assessed at baseline, day 15, and day 30 of follow-up. Results: Baseline characteristics were similar between the two groups. In the intervention group, there was a significant increase in the total hope scores after the HPP (day 15). Significant differences were still present after one month (p < 0.05). There was also a significant increase in comfort and quality of life scores in the intervention group one month after HPP (p = 0.018). Conclusions: The HPP may be an effective intervention to increase hope and improve comfort and quality of life among palliative patients. Future studies should increase sample size, diversify settings, and include longer and more detailed follow-ups.