Dysfunctional stress-coping styles may accelerate negative emotional self-efficacy in the mothers of preterm neonates. This study was conducted to determine the effect of applying problem-solving skills on stress-coping styles and emotional self-efficacy in mothers of preterm neonates. This randomized clinical trial was conducted from January 2020 to February 2021 in 4 neonatal intensive care units (NICU) of Mashhad, Iran. 60 mothers were selected using convenience sampling method and randomly assigned to control and intervention groups. The intervention group was divided into groups of 3-5 people to attend 6 sessions of at least 60 minutes held 3 times a week for two weeks and received training on problem-solving skills. The control group received routine care. Data were collected using demographic characteristic forms, problem-solving inventory, ways of Coping Questionnaire, and the emotional self-efficacy scale. The tools were initially filled out by both groups and re-completed at the end of the second week after the intervention and four weeks later. Data were analyzed using SPSS version 21 and the significance level of less than 0.05. Independent and paired t-test, Mann-Whitney, Chi-square, Fisher's exact test, repeated measures, and Bonferroni post hoc test were used. Analysis of variance with repeated measures showed that in the intervention group, there was an increase in the scores of problem-focused style (before: 37.9±6.3; immediately: 46.2±5.3; one month later: 47.5±5.6) (P<0.001), a decrease in scores of emotion-focused style (before: 44.0±6.9; immediately: 38.6±6.2; one month later: 38.0±4.4) (P<0.001), and an increase in mothers' emotional self-efficacy (before: 113.0±14.9; immediately: 130.3±10.6; one month later: 134.5±8.3) (P<0.001). Conclusion: Problem-solving skills are recommended to be used in NICU to empower mothers. Problem-solving skills are recommended to be used in NICU to empower mothers to adopt appropriate strategies for dealing with the situational stress of having a preterm neonate and to increase emotional self-efficacy.Trial Registration Number: IRCT20191211045696N1.