(1) Background: Phelan-McDermid Syndrome (PMS) in children causes significant challenges affecting social and family relationships. The purpose of this study was to explore the experience of parents with children diagnosed with PMS regarding interactions with their social environment; (2) Methods: A qualitative descriptive study was conducted. Participants were recruited using non-probabilistic purposeful sampling. In total, 32 parents of children with PMS were included. In-depth interviews and researchers’ field notes were used to collect the data. An inductive thematic analysis was performed; (3) Results: Five themes were identified: (a) challenges in the relationship as a couple; (b) challenges within the family and close social relationships; (c) challenges in the educational-school environment; (d) challenges in the health environment and with health professionals, and (e) reconnection through the PMS association. It would be beneficial for parents to create training programs on PMS in the educational and healthcare settings, to promote the participation of professionals in the PMS association and to develop care programs focusing in their physical, psychological and social health.