Introduction: Young people with chronic health conditions are among the most at risk of having poor social connections, however, little is known about their experiences of loneliness and social isolation. We aimed to describe the perspectives and experiences of loneliness and social isolation among young people with chronic physical conditions. Methods: We searched MEDLINE, Embase, PsycINFO, CINAHL, and CENTRAL from inception to May 2023 for qualitative studies that described the perspectives of loneliness and social isolation in young people aged 10-24 years with chronic physical conditions. Findings from the included studies were analyzed using thematic synthesis. Results: We included 35 studies across 12 countries involving 723 participants (56% female). Most studies (63%) were conducted in young people with cancer. Four major themes were identified: suffering from repercussions of disease (struggling with body image and physical changes, intensified disconnection while hospitalized); hindering relationships with peers and friends (missing out on formative experiences, feeling stuck behind, restrictive parental attitudes); grappling with social exclusion (facing concerns alone, bullying and ostracism); seeking social support and self-help (reliance on family, kindness and empathy from friends, developing rapport with healthcare professionals, discovering self in adversity). Conclusions: Symptoms, treatments, and hospitalizations limited young people's social participation and ability to maintain friendships, and this was compounded by social exclusion and bullying. Supportive friends, family, and healthcare professionals helped mitigate feelings of isolation. Interventions and strategies are needed to improve social support and foster meaningful connections. This can be achieved through education and awareness initiatives that promote inclusion in schools and the community, as well as efforts to enhance social support and continuity of care in hospitals.