BackgroundNurses are at risk for symptoms of Secondary Traumatic Stress (STS). The role of social support and mindfulness in predicting STS is important among nurses. This study was performed to determine the prevalence of the symptoms of STS and the role of mindfulness and social support in predicting the STS in Iranian nurses in Malayer. Methods Using a cross-sectional analytic research design, we selected 173 participants among the nurses working in public hospitals of Malayer, Iran. Secondary Traumatic Stress Scale (STSS), Freiburg Mindfulness Inventory-14 (FM I-14), and Multidimensional Scale of Perceived Social Support (MSPSS) were used for collecting the data. Results The obtained results indicated that 39.9% of the nurses had symptoms of STS and that the severity of symptoms in emergency nurses and non-emergency nurses was 41.5% and 37.9%, respectively. There was a negative correlation between mindfulness and social support (significant other, family and friends) with STS; social support (from family) negatively predicted the STS in hospital nurses. Conclusion Based on the obtained results, the relationship between mindfulness, social support and STS and the role of social support from family in predicting the STS in Malayer nurses were confirmed. Thus, it is necessary to develop support systems for nurses who are at risk for STS.