As at a high-risk group of psychological distress, nurses generally experience varying degrees of stress, anxiety, and depression. This paper identifies the positive factors that may negatively regulate the psychological pain of clinical nurses and their mechanisms of action, providing reliable references for clinical nurse support management. The effects and mechanisms of hope and the two components of grit consistency of interest and perseverance of effort) on clinical nurses’ psychological distress (depression, anxiety, and stress) were observed in this study. A total of 635 Chinese clinical nurses (90.4% female) completed an anonymous questionnaire for the survey. As expected, hope, consistency of interest, and perseverance of effort were negatively correlated with the three indicators of psychological distress (r = −0.21 ~ −0.38, p < 0.01). Path analysis results showed that hope significantly mediated the negative effect of consistency of interest on psychological distress, with an effect of 12.96%. Hope also covered up the perseverance of effort on psychological distress, the effect of 110.63%. In the influence of consistency of interest and perseverance of effort on psychological distress, hope contributed a vital mediating. Based on these results, it can be concluded that grit and hope have protective effects on psychological distress in clinical nurses. Significantly increasing the level of hope or grit may effectively prevent and reduce psychological distress in clinical nurses.