Feelings of social connection are important to maintain physical and psychological well-being. Perceived social isolation, or loneliness, is the subjective experience of feeling socially isolated and may be a direct threat to our health. During recent years, an increasing amount of people report high levels of loneliness, potentially brought on by the COVID-19 pandemic and its restrictions. Recent research suggests that the brain’s default mode network (DMN), a neural network active at wakeful rest, is related to these experiences. This paper aimed to systematically review alterations in the DMN in socially connected and lonely individuals. I searched PubMed and Scopus to find studies using self-report measures of social connection or loneliness, and functional or structural neuroimaging methods on healthy adults. Nine studies were included in this review. Generally, core regions of the DMN typically involved in episodic memory and self-referential processing showed increased activity in lonely individuals and decreased activity in socially connected individuals. These findings may reflect how lonely individuals ruminate about past social events while socially connected individuals attend less to the self. However, methodological heterogeneity between studieslimits the conclusions that can be drawn based on these results.