Background: A low HRQOL can be a risk factor for future cardiovascular events in patients with hypertension. Therefore, HRQOL should receive attention and be improved in the treatment of hypertension. The purpose of this study was to investigate if the association between treatment groups and Health-Related Quality of Life (HRQOL) of hypertension mediated by self-management, and to determine which factors of hypertension self-management influenced HRQOL. Methods: Hypertensive patients were selected by multi-stage stratified samping from “1+1+N” Physicians intervention (PI) group and the conventional management (CM) group in 5 communities of Xiamen, China. Patients were cross-sectionally assessed by validated self-reports using self-management Behavior Rating Scale and Quality of Life Instruments for Hypertension. A structural equation modeling (SEM) and a path analytic model were used to assess if the association between treatment groups and HRQOL was mediated by self-management. Results: A total of 1207 patients were included, of whom 48.55% were in the PI group. The average score of the HRQOL scale was 86.68, and the average score of the PI group was higher than the CM group (87.35 vs 86.04, respectively). Similar findings were observed for the self-management scale, in which the average score of the PI group was higher than the CM group (76.32 vs 72.00, respectively). Patients in the PI group had higher levels of self-management compared to the CM group except for management of emotion. SEM showed that the association between treatment groups and HRQOL was significantly mediated by self-management (a*b, 95% confidence intervals CI: 0.02,0.07) and that the single mediator (self-management) model explained 76.67% of the intervention effect. In the multivariable mediation model, the association between treatment groups and HRQOL was significantly mediated by management of medication adherence, sport and diet.Conclusions: The findings presented good evidence supporting that treatment groups are linked to HRQOL of hypertension via self-management. Specifically, management of medication adherence, sport, diet, and emotion are important for improving HRQOL.