Background: The family of leukemia patients, due to their caring role, often feels psychological distress. A practical need-based program carefully considers the set of requirements of nursing service recipients. This paper illustrates the efficacy of a designed family-need-based program on relieving stress, anxiety, and depression of family caregivers of leukemia patients. Methods: In this controlled trial, sixty-four family caregivers of leukemia patients referring to a medical center in Iran were recruited by convenience sampling and randomly divided into study and control groups. The study group attended a designed need-based program. The control group did not receive the intervention. Stress, anxiety, and depression of both groups were simultaneously measured and compared in three time-points using the scale of stress, anxiety, and depression (DASS-42). Data were analyzed using descriptive and inferential statistics. Results: Before the program, the average scores of stress, anxiety, and depression were 31.16 ± 4.14, 21.37 ± 6.31, and 27.56 ± 4.24 for the study group and 31.09 ± 4.48, 20.34 ± 6.56, and 28.78 ± 4.72 for the control group. After the program, the average scores of stress, anxiety, and depression were 10.56 ± 3.37, 6.75 ± 2.99, and 7.37 ± 2.76 for the study group and 34.87 ± 2.51, 23.65 ± 4.96, and 32.56 ± 3.49 for the control group, respectively. Results of the independent t test indicated no considerable difference before the program (P > 0.05) and a significant difference after the program (P < 0.001) between the two groups. Conclusion: This family-need-based program can decrease the level of stress, anxiety, and depression of the family caregivers of leukemia patients and may potentially alleviate the psychological distress of family caregivers over their caring role.