Although there is a growing body of literature on the consequences of work alienation, its antecedents have not received the same attention. Therefore, there is a need to examine elements affecting work alienation, the examination of which has been a preoccupation amongst both organisations and scholars. Drawing on the Social Exchange Theory and Self-Determination Theory, we aim to investigate the relationship between leader-member exchange, work alienation, and the mediation role of self-regulation on this relationship. We also consider whether tenure moderates the relationship between leader-member exchange and work alienation. To achieve the aim of the study, the quantitative research method is adopted by collecting data from 310 public and private sector employees and middle managers in Turkey. The partial least squares approach is employed to test the conceptual model, and multi-group analysis is used to examine whether the relationship differs with sector. The results reveal that leader-member exchange negatively affects work alienation, and self-regulation mediates this relationship. Tenure has a moderating effect on the relationship between leader-member exchange and self-regulation. Multi-group analysis results demonstrate a higher impact of leader-member exchange on self-regulation in the public sector than in the private sector. Implications, limitations, and future studies are drawn from the results.