Background: Pregnancy and the arrival of a new baby is a time of great transition and upheaval. Women often experience social isolation and loneliness at this time and may develop depression, particularly in the postnatal period. Qualitative studies have reported that loneliness is also a feature of perinatal depression. However, until now there has been no attempt to synthesise research exploring the links between loneliness and perinatal depression. This study’s aim was to explore existing qualitative evidence to answer two research questions: What are the experiences of loneliness for women with perinatal depression? What helps and what makes loneliness worse for women with perinatal depression? Methods: A qualitative meta-synthesis retrieved primary qualitative studies relevant to the research questions. Four electronic databases were systematically searched (Ovid MEDLINE®; PsycINFO; Embase; Web of Science). Papers were screened according to pre-defined inclusion criteria and assigned a quality score. Thematic analysis was used to identify major overarching themes in the literature. Results: Twenty-seven relevant qualitative studies were included. Themes relating to the interaction between perinatal depression and loneliness included self-isolation and hiding symptoms due to stigma of perinatal depression and fear of judgement as a ‘bad mother’; a sudden sense of emotional disconnection after birth; and a mismatch between expected and actual support provided by partner, family and community. There was also a double burden of loneliness for women from disadvantaged communities, due to increased stigma and decreased social support. Validation and understanding from healthcare professionals, peer support from other mothers with experience of perinatal depression, and practical and emotional family support were all important factors that could ameliorate loneliness. Conclusions: Loneliness appears to play a central role in the experience of perinatal depression based on the frequency with which it emerged in women’s accounts. The findings provide a foundation for the development of further theories about the role of loneliness in perinatal depression and evidence in which future psychological and social intervention design processes can be rooted. Addressing stigma and offering culturally appropriate professional and peer support are potential targets for interventions that could help women with perinatal depression, particularly in disadvantaged communities, feel less lonely. Trial registration: Prospero registration: https://www.crd.york.ac.uk/prospero/display_record.php? RecordID = 251,936.