Previous studies conducted during the COVID-19 pandemic found an increased risk of loneliness due to measurements taken by governments to limit social interaction. The current study addresses the relationship between loneliness and both positive and negative mental health in times of the COVID-19 pandemic and the role of psychological flexibility. Data was collected in the Dutch general population (18+) with two online questionnaires (T1-T2), with an interval of four weeks. A sample of 340 participants varying in age from 18 to 83 years (Mage(SD): 52.83 (13) and 61.8% female, filled in both questionnaires. Loneliness and (the six core processes of) psychological flexibility were measured at T1 and negative mental health (depression, anxiety and stress) and positive mental health (psychological, emotional and social well-being) at T2. Regression analyses indicated a positive prospective relation between loneliness and negative mental health and a negative prospective relation between loneliness and well-being. Psychological flexibility had a moderating effect on the relation between loneliness and negative mental health but not on the relation between loneliness and well-being. Looking at the six core processes of psychological flexibility, only acceptance was a significant moderator of the relation between negative mental health and loneliness.We conclude that while it has yet to be determined whether the moderating relationships found in this study hold beyond COVID-19 conditions, the findings do provide support for the benefits of psychological flexibility to intervene in situations where external circumstances or psychological challenges are beyond one's control.