Background: Cultural intelligence has been described as an essential intelligence for the 21st century that can increase students' adaptability, problem-solving skills, and influence their performance and learning vitality. Aim of this study was to investigate the relationship between cultural intelligence and academic vitality with self-directed learning among nursing students. Design: Descriptive, correlational study design was adopted. Setting: The study was conducted at Faculty of Nursing, Tanta University. Subjects: All fourth year nursing students (n=295) were included. Tools: Three tools for data collection were used to achieve the aim of this study; Cultural Intelligence Scale, Academic Vitality Questionnaire and Self-Directed Learning Instrument (SDLI). Results: As a result of the conducted study revealed that there is a high level of culture intelligence and academic vitality with moderate level of self-directed learning among nursing students. There were significant positive correlation between self-directed learning (r= 0.33) and its aspects including, self-management (r= 0.72), desire for learning (r= 0.58) and self-monitoring (r=0.52) with cultural intelligence and academic vitality (P<0.01). Conclusion: Self-directed learning seems to be a phenomenon that is influenced by many factors such as cultural intelligence and academic vitality. Recommendations: this study suggests that academic vitality and culture intelligence should be considered together when self-directed learning is conducted to improve nursing students' academic performance. Workshops should be held in order to promote self-directed learning among students.