Aim The aim of this multi‐centre cohort study was to investigate the association of non‐surgical periodontal therapy (NST) on the oral health‐related quality of life (OHRQoL) in general and related to severity of periodontal disease and treatment modalities. Materials and Methods One hundred and seventy‐two patients with periodontal disease from 18 dental practices were measured before and 6–8 weeks after NST using a standardized and validated OHRQoL instrument (Oral Health Impact Profile‐G14, OHIP‐G14). Another questionnaire was filled out by the dentists to evaluate the influence of treatment modalities and disease severity. Results Overall, the mean value of the OHIP baseline improved significantly after NST (p < 0.0001). Furthermore, a significant negative association between the severity of periodontitis and OHRQoL could be detected, and only patients with moderate and severe periodontitis showed a significant improvement of OHIP mean values (p < 0.0001). The results also indicated a significant association of the practitioners (p = 0.0362) as well as treatment modalities (favouring systemic antibiotics, p = 0.0066) regarding the improvement of the patients' OHRQoL. Conclusion This study showed that NST is positively associated with patients' oral health‐related quality of life. This association seems to depend on the disease severity and caregiver and treatment modality.