Background: Being not fully explored, this study aimed to assess the impact of anticoagulation management on the Health-Related Quality of Life (HRQoL) and Psychological Distress (PD) of cardiac patients on warfarin therapy in Egypt. Methods: Using Arabic versions of the World Health Organization Quality of Life Assessment Brief Form (WHOQOL-BREF) and Hospital Anxiety and Depression Scale (HADS), patients on warfarin were evaluated across four WHOQOL-BREF domains: social, psychological, environmental, and physical. PD, differentiating between anxiety and depression, was assessed through HADS. Results: We assessed 302 patients (57% of participants were males). The social domain had the highest mean score (56.05±16.899), followed by psychological (48.89±18.83), environmental (46.26±13.809), and physical domains (36.23±18.575). Depression mean score (9±8.401) exceeded anxiety (6.83±7.939), with 51% experiencing depression and 40.4% anxiety. Positive correlations were found among WHOQOL-BREF domains, with a strong negative correlation between anxiety and depression (r = -0.93, p < 0.001). Significant associations were noted between comorbidities, employment status, marital status, and HRQoL/PD indicators. Comorbidities other than cardiovascular diseases (CVD) and employment status significantly correlated with physical and social domains (p < 0.001 each). Marital status correlated significantly with psychological and social domains (p < 0.001 each), and depression and anxiety were significantly correlated with marital status (p = 0.031 and p = 0.049, respectively). Conclusion: participants reported higher HRQoL scores in the social domain, with depression prevalence exceeding anxiety. Socio-demographic and clinical factors significantly influenced HRQoL and PD, providing insights into factors affecting CVD patients' well-being on anticoagulation in a sector of Egyptian population.