Abstract Purpose To comprehend the complex relationship between symptoms and health-related quality of life (HRQoL) in patients with diffuse glioma, we applied symptom network analysis to identify patterns of associations between depression, cognition, brain tumor-related symptoms, and HRQoL. Additionally, we aimed to compare global strength between symptom networks to understand if symptoms are more tightly connected in different subgroups of patients. Methods We included 256 patients and stratified the sample based on disease status (preoperative vs. postoperative), tumor grade (grade II vs. III/IV), and fatigue status (non-fatigued vs. fatigued). For each subgroup of patients, we constructed a symptom network. In these six networks, each node represented a validated subscale of a questionnaire and an edge represented a partial correlation between two nodes. We statistically compared global strength between networks. Results Across the six networks, nodes were highly correlated: fatigue severity, depression, and social functioning in particular. We found no differences in GS between the networks based on disease characteristics. However, global strength was lower in the non-fatigued network compared to the fatigued network (5.51 vs. 7.49, p < 0.001). Conclusions Symptoms and HRQoL are highly interrelated in patients with glioma. Interestingly, nodes in the network of fatigued patients were more tightly connected compared to non-fatigued patients. Implications for Cancer Survivors We introduce symptom networks as a method to understand the multidimensionality of symptoms in glioma. We find a clear association between multiple symptoms and HRQoL, which underlines the need for integrative symptom management targeting fatigue in particular.