Syncope is among the most common paroxysmal disorders in children and adolescents. Vasovagal syncope is the most common syncope in children and adolescents. The aim of this study was to evaluate the impact of self-care recommendations with and without tilt training on the Quality of Life (QoL) of children and adolescents with syncope. This randomized controlled clinical trial was conducted in Isfahan, Iran, from April 2017 to June 2021 and included 120 patients with syncope. Eligible children and adolescents (aged 6-18 years) who met inclusion criteria were recruited by the simple sampling method and then assigned randomly into two groups. The intervention group (n = 60) received routine self-care recommendations such as dietary advice, behaviors to prevent syncope, and counter-pressure maneuvers along with tilt training, while the control group (n = 60) received self-care recommendations without tilt training. The education training included two face-to-face sessions, each of which lasted for 45-60 min. Then, both groups were followed up by telephone (once a month) for six months. A researcher-made self-care questionnaire and Pediatric Quality of Life Inventory (PedsQL™ 4.0) were completed for both groups before and after the intervention. Data were analyzed using descriptive and inferential statistical methods. The Wilcoxon test results showed a significant difference in the mean scores of physical functioning, emotional functioning, social functioning, school functioning, psychosocial functioning, understanding of health, and total QoL in the intervention and control groups before and after the intervention (p < 0.05). Also, the paired t-test results showed a significant difference in the mean scores of self-care domains and total self-care in the intervention and control groups before and after the intervention (p < 0.05). Self-care recommendations with and without tilt training can improve QoL in children and adolescents with syncope.