In a time of rapid global decline in mental well-being and growing awareness of the limitations of mainstream depression treatments, psilocybin may offer therapeutic potential that has previously been overlooked. As a psychedelic compound that binds to serotonin receptors, psilocybin increases excitability in specific brain regions, promoting more flexible global communication between networks and reducing the grip of maladaptive patterns. Psilocybin is being investigated in clinical settings for its effects on various mental health conditions, particularly its efficacy in treating depression. This systematic review analyzes current research on resting-state neural activity and connectivity changes following psilocybin administration. It examines three recent fMRI studies, retrieved from the Scopus and Web of Science databases, on psilocybin treatment for major depressive disorder (MDD) and treatment-resistant depression (TRD), focusing on changes in both brain activity and symptom severity. The findings indicate that psilocybin may reduce depressive symptoms through modulation of global neural connectivity, with effects that seem to persist over time. Some converging results suggest that psilocybin induces global reorganization in the brain, with changes in connectivity, hierarchy, and flexibility of networks like the default mode network (DMN) and cingulate cortex in particular. Further research is needed to address current limitations, such as small sample sizes, methodological differences, and confounding factors.