Abstract Background Chronic liver disease is primarily caused by hepatitis C virus (HCV). HCV produces extrahepatic psychiatric problems. So, patients with CHC who received sofosbuvir-based direct-acting antiviral agents (DAAs) were evaluated for psychiatric manifestations, specifically depression and anxiety symptoms. Additionally, evaluate the impact of gender on psychiatric manifestations of sofosbuvir-based DAAs and identify their potential risk factors for psychiatric manifestations. In this prospective study, 170 CHC patients without prior treatment received DAA therapy who categorized into 2 groups, group 1 comprised male participants (Nb = 97), and group two comprised female participants (Nb = 73). All participants were evaluated with the five-factor model of personality (SIFFM), Hamilton Depression Rating Scale (HDS), and Hamilton Anxiety Rating Scale (HAS) at baseline and repeated follow up until 3 months after treatment end. Results Our findings indicated that, a progressive decline in the mean HADS-A and HADS-D scores between baseline (before treatment) and consequence follow-up (during and after treatment) measurements without significant difference regarding gender. No statistically significant difference between the groups regarding the mean values of SIFFM. High levels of extraversion were more likely to increase depression levels. Conclusions DAA treatment significantly improved anxiety and depression symptoms in CHC patients. Gender did not affect sofosbuvir-based DAA psychiatric symptoms. High extraversion increased depression risk.