It is well known that the quality of life (QoL) of patients with chronic hepatitis C (HCV) is lower than that of the general population and that therapy with direct-acting antivirals (DAA) for HCV is safe and effective. However, data on the QoL of patients are scanty. The purpose of this study was to assess the effect of DAA drugs on patients' QoL. The literature included in this meta-analysis was due in March 2021. The random effect model of heterogeneous data and the fixed effect model of homogeneous data were used to analyze the data. QoL had to be evaluated using the Short Form Health Survey (SF-36) questionnaire with at least one measure at baseline (T0) and one measure at 12 weeks (T12) or 24 weeks (T24) after the end of therapy. The meta-analysis included eight studies, which involved 1,619 patients. At T12, the meta-analysis showed all items of the SF-36 questionnaire improved from the pretreatment to post-treatment period and reached statistical significance (p < 0.05) except for the bodily pain (mean difference: 1.16, 95%CI -0.43-2.74) and role limitations-emotional (mean difference: 4.10, 95%CI -1.32-9.52). However, after subgroup analysis (whether ribavirin was being used or not), the bodily pain domain (mean difference: 3.34, 95%CI 1.03-5.65) became statistically significant again. At T24, the results indicated that all items of the SF-36 questionnaire improved from the pretreatment to the post-treatment period and reached statistical significance (p < 0.05) except for the role limitations-emotional domain (mean difference: 4.50, 95%CI -2.66-11.66). There is evidence indicating that DAA therapy is accompanied by an improvement in QoL. Patients receiving DAA medication have a clinically relevant improvement in most domains of the SF-36 questionnaire at T12 or T24, except for a few aspect may including role limitations-emotional.