Background: Critical care nurses (CCNs) face difficulties and stress when caring for patients with delirium, and the level of delirium-related stress may be related to gaps in their knowledge and skills. Aim: This study aimed to assess the impact of a psychoeducational and relaxation program on reducing the stress of CCNs caring for patients with delirium in intensive care units (ICUs) in Taiz city, Yemen. Methods: From June to the end of December 2022, a quasi-experimental study was conducted among 60 CCNs from two ICUs of Al-Thawra Hospital in Taiz. Demographic characteristics were collected using a pre-designed data collection sheet, and the levels of CCNs’ stress were measured using the Delirium Nursing Stress Scale (DNSS). To assess the impact of the developed psychoeducational and relaxation program, stress levels were measured before and after the program, as well as at a 3-month follow-up for long-term impact. The association of demographic characteristics with delirium-related stress was also studied. Data were then analyzed using appropriate statistical tests at a significance level of <0.05. Results: Before the program, the mean score of CCNs’ stress was 60.48 ± 9.51, corresponding to a moderate stress level of 86.7%. However, this score was significantly reduced to 30.98 ± 4.35 immediately after the program and was sustained at 33.13 ± 5.31 3 months after the program, corresponding to a mild stress level. The highest mean score of CCNs’ stress related to caring for patients with delirium was observed before the program for all causes of stress on the DNSS, being 4.95 ± 1.77 for the nursing environment, 9.37 ± 2.16 for relationships with peers, 14.40 ± 4.02 for knowledge about delirium, and 31.77 ± 5.78 for nursing practice and work. However, the mean stress scores related to all these causes showed a significant reduction after the program (2.85 ± 0.95, 4.70 ± 1.33, 7.20 ± 1.67, and 16.23 ± 2.80, respectively) and at the 3-month follow-up (3.15 ± 1.05, 4.95 ± 1.23, 7.67 ± 1.66 and 17.37 ± 3.57, respectively). On the other hand, the mean score of total stress for all DNSS items showed a significant reduction from 60.48 ± 9.51 before the program to 30.98 ± 4.35 after the program and 33.13 ± 5.31 at the 3-month follow-up. There were no statistically significant differences in the mean scores of delirium-related stress before and after the program, or at the 3-month follow-up for any of the demographic characteristics of CCNs. Conclusion: Psychoeducational and relaxation programs have a positive impact on stress reduction in CCNs caring for patients with delirium, improving the standard of care provided to these patients. Regular assessment of CCNs for delirium-related stress and educating them to acquire knowledge and skills are recommended to reduce this stress when caring for delirious patients.