Social networking is proliferating globally and in Vietnam, but this led to several negative aspects of adolescents’ health, including physical activity, sleep quality, and depressive and anxiety symptoms. This study aimed to identify the relationship between social media usage and examine risk factors (Fear of Missing out and Risk of Neglect) on social media usage, and the overall quality of life and mental health among individuals actively using social media networks. An online cross-sectional study was conducted in three cities in Vietnam (Hanoi, Tuyen Quang, and Can Tho) from September through to October 2021. A structured questionnaire assessed for characteristics of social media use and other associated factors. 1891 participants were recruited, with 98.4% having access to social media. s. Factors like “PHQ-9 score”, “Problematic Internet use”, and “Time average used social media per day”, were negatively associated with the EQ5D5L Index. By contrast, “Gender”, and “Using smartphone” were positive factors of the EQ5D5L Index. “FOMO score” and “self-harm and suicide” were positive factors of the PHQ-9 score while “Using smartphone” was negative. In terms of self-harm and suicide, “FOMO score” and “Problematic Internet use” were positive factors, by contrast, “Using smartphone” was a negative factor. This is the first study to examine social media addiction among Vietnamese adolescents, its relationship with FOMO score, stresses associated with rejection and neglect, and the overall quality of life. Our results highlighted there is a relationship between FOMO score and impaired overall quality of life, increased depressive symptoms, and an association between stresses relating to negative rejection and FOMO score.