Both clinical and non-clinical individuals are influenced differently depending on their levels of positive orientation and psychological distress. Firstly, the present study investigated the significant differences between clinical and non-clinical individuals on positive orientation and psychological distress. Secondly, the present study examined the predicting role of positive orientation on psychological distress. Lastly, this study investigated whether the presence or absence of diagnosed psychological disorder moderates the relationship between positive orientation and psychological distress. A total of 323 non-clinical and 290 clinical samples were recruited. Findings showed that there are significant differences between clinical and non-clinical samples in terms of positive orientation and psychological distress. The findings for clinical sample showed that positive orientation, self-esteem, and life satisfaction can significantly predict stress, anxiety, and depression negatively, whereas for the non-clinical samples, results showed that positive orientation and self-esteem can significantly predict stress, anxiety, and depression negatively. Moderation analysis indicated that the relationship between positive orientation and stress, and the relationship between self-esteem to anxiety, depression, and stress are amplified with the presence of diagnosed psychological disorder. In conclusion, this indicates potential psychological intervention development in utilising positive orientation to assist clients with or without clinical conditions. Preventive measures towards psychological distress were also discussed.