Living with persistent physical symptoms of an acute COVID-19 infection has a substantial impact on individuals' everyday lives. The identification of potential therapeutic targets for Post-COVID-19 Syndrome (PCS) or “Long-COVID” that can be utilised to reduce the impact of symptoms, is necessary to support effective rehabilitation. Self-compassion and psychological flexibility are thought to be important constructs to consider when understanding how individuals approach the management of long-term health challenges. The present study investigated the extent to which self-compassion and psychological flexibility moderate the relationship between physical symptoms and their impact on daily life. One-hundred and five participants (91 females) who were living with PCS after an acute COVID-19 infection, completed measures to assess PCS physical symptom prevalence as well as measures to assess impact on daily life, self-compassion and psychological flexibility. Two parallel moderation analyses showed that self-compassion and psychological flexibility significantly moderated the relationships between physical symptom presentation and their psychosocial impact. This research highlights the buffering effects of self-compassion and psychological flexibility and the need to consider these psychological therapeutic targets, as part of PCS multidisciplinary rehabilitation.