Objectives Mindfulness, positive affect, and compassion may protect against psychological distress but there is lack of understanding about the ways in which these factors are linked to mental health. Network analysis is a statistical method used to investigate complex associations among constructs in a single network and is particularly suitable for this purpose. The aim of this study was to explore how mindfulness facets, affect, and compassion were linked to psychological distress using network analysis. Methods The sample ( n = 400) included equal numbers from general and student populations who completed measures of five mindfulness facets, compassion, positive and negative affect, depression, anxiety, and stress. Network analysis was used to explore the direct associations between these variables. Results Compassion was directly related to positive affect, which in turn was strongly and inversely related to depression and positively related to the observing and describing facets of mindfulness. The non-judgment facet of mindfulness was strongly and inversely related to negative affect, anxiety, and depression, while non-reactivity and acting with awareness were inversely associated with stress and anxiety, respectively. Strong associations were found between all distress variables. Conclusions The present network analysis highlights the strong link between compassion and positive affect and suggests that observing and describing the world through the lens of compassion may enhance resilience to depression. Taking a non-judging and non-reacting stance toward internal experience while acting with awareness may protect against psychological distress. Applicability of these findings can be examined in experimental studies aiming to prevent distress and enhance psychological well-being.