Background: Empty-nest youth are among the most vulnerable populations in society and they are prone to social isolation. Social isolation has a significant impact on empty-nest youth themselves and the society. Through an in-depth understanding of the main factors of social isolation among empty-nest youth in East China, this study aim to address their social isolation, ensure their psychological health and quality of life, and promote social integration. Method: This study used descriptive qualitative research to conduct semi-structured interviews with 15 empty-nest youth between August and October 2021. We used directed content analysis on the resulting data. Result: By combining, generalizing, and refining, we finally derive two main themes and eleven sub-themes. According to attribution theory, we divide results into internal factors (personality traits, internet dependence, upwards comparison mindset, social cognitive bias, lack of social adaptation ability, inadequate social skill) and external factors (social network relationship disconnection, insufficient urban concern, indifferent interpersonal relationship, heavy economic burden, work factor). Conclusion: Factors contributing to social isolation among empty-nest youth are multifaceted. The study recommends that managers take appropriate measures to reduce the level of social isolation among empty-nest youth, safeguard their psychological health and quality of life, and promote social integration.