Background: High mobile-phone dependency may cause cognitive, emotional, and academic impairments among students; hence, proper therapies should be performed to prevent the risk. Objectives: The present study aimed to investigate the effectiveness of the nomophobia therapy package on self-esteem and nomophobia symptoms in high school students. Methods: The research method was quasi-experimental with a pre-test, post-test, and follow-up design and a control group. The statistical population included all the students showing nomophobia symptoms who were in high schools in Isfahan in the academic year of 2018 - 2019. Using purposive sampling, we selected 30 students willing to participate in the project and randomly divided them into experimental (n = 15) and control (n = 15) groups. The research instrument included Nomophobia Questionnaire and Self-Esteem Questionnaire. The experimental group underwent eight sessions (75-minute sessions per week) of nomophobia therapy. The follow-up was performed after two months. Data were analyzed by descriptive and inferential statistics, such as mean, standard deviation, and repeated measures ANOVA. SPSS version 23.0 was further used to analyze the data. Results: The mean ± SD of the post-test scores of self-esteem and nomophobia symptoms were (19.26 ± 3.34) and (50.60 ± 5.07) in the experimental group and (13.46 ± 2.47) and (71.63 ± 8.47) in the control groups. The difference between the scores of the experimental and control groups in the pre-test was not significant (all P-values were > 0.05). Also, the post-test scores did not have a significant difference from the follow-up scores (all P-values were > 0.05). Nomophobia therapy effectively increased self-esteem in students with nomophobia symptoms in the experimental group (P = 0.0001). The training intervention sessions decreased the nomophobia symptoms of high school students in the experimental groups compared to the control group (P = 0.0001). Conclusions: According to research findings, nomophobia therapy was an efficient therapy for improving self-esteem and reducing nomophobia symptoms in students who suffer from the syndrome.