BACKGROUND: Weight stigma is a fundamental cause of health inequality. Body positivity may be a counterbalance to weight stigma. Social media is replete with weight-stigmatizing content and is a driver of poor mental health outcomes; however, there remains a gap in understanding its potential to mitigate the prevalence and impact of harmful messaging and to promote positive effects on a large scale. OBJECTIVE: We selected musical artist Lizzo, whose brand emphasizes body positivity and empowerment, for an instrumental case study on the discourse on social media and specifically Instagram. We focused on 3 domains, including body positivity, physical health, and emotional well-being. These domains challenge social norms around weight and body size and have the potential to positively affect the physical and psychological health of people with diverse body sizes. METHODS: We evaluated posts by Lizzo, comments from Instagram users, and replies to comments over a 2-month period (October 11 to December 12, 2019). Two coders rated Lizzos posts and Instagram users comments for their sentiments on the 3 domains. Replies to Instagram users comments were assessed for their reactions to comments (ie, did they oppose or argue against the comment or did they support or bolster the comment). Engagement metrics, including the number of likes, were also collected. RESULTS: The final sample included 50 original posts by Lizzo, 250 comments from Instagram users, and 1099 replies to comments. A proportion of Lizzos content included body positive sentiments (34%) and emotional well-being (18%); no posts dealt explicitly with physical health. A substantial amount Instagram users comments and replies contained stigmatizing content including the use of nauseated and vomiting emojis, implications that Lizzos body was shameful and should be hidden away, accusations that she was promoting obesity, and impeachments of Lizzos health. In spite of the stigmatizing content, we also discovered content highlighting the beneficial nature of having positive representation of a Black woman living in a larger body who is thriving. Moreover, analysis of the discourse between users illustrated that stigmatizing expressions are being combated online, at least to some degree. CONCLUSIONS: This study demonstrates that Lizzo has exposed millions of social media users to messages about body positivity and provided more visibility for conversations about weight and shape. Future research should examine the extent to which body positive messages can lead to greater acceptance of individuals living in larger bodies. Instagram and other social media platforms should consider ways to reduce body-shaming content while finding ways to promote content that features diverse bodies. Shifting the landscape of social media could decrease stereotypes about weight and shape while increasing dialog about the need for greater acceptance and inclusion of people with diverse bodies.