Purpose: Dhikr and prayer reduce pain and improve a patient's vital signs. However, the interactions among these require further clarification in patients undergoing appendectomy. This study aimed to assess the effects of the combination of dhikr and prayer on pain, pulse rate, respiratory rate, and oxygen saturation. Study design: Quasi-experimental design. Method: Pain, pulse, respiratory rate, and oxygen saturation were measured via clinical examination immediately after leaving the recovery room at 1 and 2 hr after surgery in both the experimental and control groups. In total, 88 eligible participants were allocated to two groups: participants who received both dhikr and prayer ( n = 44), and those who received routine care without analgesic therapy ( n = 44). The chi-square test, independent t test, and general equation model were employed. Results: Respondents showed a significant interaction between group and time to decrease in pain, pulse, respiratory rate, and improved oxygen saturation, except for pain within 1 hr. The differences in all outcome scores between the groups after 1 and 2 hr were statistically significant, except for oxygen saturation after 1 hr. Conclusion: The combination of dhikr and prayer effectively decreased pain and improved vital signs. This helped nurses implement this procedure by promoting an essential culture of spiritual care for appendectomy patients.