Socio-psychological factors such as fear of recurrence and presence of social support may affect quality of life (QOL) of cancer patients. Identifying mediating factors that impact QOL are crucial for targeting vulnerability in patients undergoing cancer treatments. The study purpose was therefore to determine relationships between presence of fear of cancer recurrence and QOL of patients, with the mediating role of social support. A predictive correlational design was used to conduct the study with 300 patients with cancer who were undergoing chemotherapy, radiotherapy, or surgery at two medical centers in Tehran. Measures included a demographic information form, the Fear of Cancer Recurrence Inventory (FCRI), the European Organization for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), and the Multidimensional Scale of Perceived Social Support (MSPSS). Data analyses included descriptives, and path analysis analyses. Higher fear of cancer recurrence predicted lower QOL (β = -0.60, p < 0.001). Moreover, individuals with lower fear of cancer recurrence also perceived higher social support (β = 0.32, p < 0.001). Additionally, individuals with higher perceived social support also reported better QOL (β = 0.30, p < 0.001). Perceived social support plays a significant mediating role in the relationship between the fear of cancer recurrence and QOL in patients undergoing active cancer treatment. Enhancing social support among cancer patients may contribute to enhanced QOL, and as does reducing fears associated with disease recurrence.