The Hepatitis C Virus (HCV) infection often associates medical and mental health conditions which lead to increased levels of distress. Our study aimed at assessing the level of perceived stress on a sample of 90 HCV infected patients treated with Direct-Acting Antiviral (DAA) agents for 12 weeks, and its possible correlations with clinical and evolutionary elements. The evaluation was conducted in three phases: before administration of the DAAs (BSL), at the End of the Treatment (EOT), and 24 weeks after the BSL (Sustained Viral Response—SVR). The perceived stress was measured using the Perceived Stress Scale (PSS). The efficiency of the DAA treatment reduced the levels of stress (98.99% moderate and high stress at BSL to 70.00% at SVR). It was observed, for the entire study period (BSL to SVR), that the decrease in the perceived stress severity was significantly associated with demographic items such as gender (p < 0.01), urban environment (p < 0.001), the age of the subjects (p < 0.05), and clinical data such as F4 degree of fibrosis (p = 0.001) and overweight or obesity class II (p < 0.01). The perceived stress is directly associated with the severity of the HCV infection, and it could be significantly lowered by an efficient therapeutic approach, as DAAs are nowadays.