Background Social media use among adolescents has been linked to mental health and well-being. However, most of the studies investigating this association focus primarily on frequency and duration of use, providing little knowledge of how various types of social media activities may be differentially linked to mental health and well-being. A recent narrative review highlighted that self-presentation may be an important factor to investigate in order to better understand the link between use of social media and well-being among adolescents. The aims of the present study were to investigate the association between focus on self-presentation on social media and mental health and quality of life among adolescents. Specifically, we aimed to investigate the overall and gender-stratified associations between self-presentation and symptoms of depression and anxiety, as well as a general measure of quality of life. Methods This study employs a cross-sectional survey-based design. A total of 513 (56%) students enrolled at a senior high school in Norway participated. The mean age of the participants were 17.1 years (1.1 standard deviations), and 58% were boys. Associations between focus on self-presentation on social media and symptoms of anxiety and depression and quality of life were investigated using blobbograms, standardized mean difference and gender-specific linear regression models. Results Overall, a high focus on self-presentation on social media was associated with more mental health problems and reduced quality of life. The strength of the associations with symptoms of depression (0.64 standardised mean difference (SMD)) and anxiety (0.60 SMD) was medium to large, while it was medium for quality of life (-0.45 SMD). In gender-stratified analyses, the association was similar for boys and girls in relation to symptoms of anxiety. For symptoms of depression, the association was stronger for girls compared to boys. Focus on self-presentation on social media was only significantly associated with quality of life among girls. Conclusions In sum, our findings are preliminary evidence of a medium strong relationship between focus on self-presentation on social media and symptoms of anxiety and depression for both genders, albeit with potential important gender differences. Potential implications and public health relevance of the findings are discussed.