This study investigates the effects of the social comparison orientation in social networking sites on psychological well-being. In particular, it examines the mediation effect of perceived social support and self-esteem in the relationship between social comparison orientation and psychological well-being. Data were collected through an online survey with 236 participants in South Korea. The results showed that social comparison orientation negatively influenced psychological well-being. In the relationship between social comparison orientation and psychological well-being, perceived social support had no mediation effect, self-esteem had a significant negative mediation effect, and perceived social support and self-esteem had a negative serial mediation effect. The social comparison orientation in social networking sites could elicit negative emotions, which decrease perceived social support, self-esteem, and psychological well-being. Theoretical and practical implications as well as suggestions for future studies are discussed in detail.