Background and Objectives: Despite the critical importance of effective healthcare management for patients with multimorbidity, robust and reliable tools for assessing health-related quality of life in Lithuania remain scarce. We aim to identify trends in the quality of life of patients with multimorbidity and to evaluate the effectiveness of the Lithuanian version of the EuroQol EQ-5D-5L questionnaire. Materials and Methods: The study included patients between the ages of 40 and 85 (N = 498) who had at least two chronic conditions, arterial hypertension being a prerequisite. The participants completed a comprehensive set of questionnaires specifically prepared for the TELELISPA “Improved healthcare quality for patients with multimorbidity in Lithuania” project which included the translated EQ-5D-5L questionnaire. The predictive validity of the EQ-5D-5L questionnaire was assessed using correlations with the SF-36 and EQ-VAS scores, a random forest regression model. Reliability was evaluated using Cronbach’s alpha and inter-item correlations. Trends in the quality of life in different patient groups were assessed with Chi-square tests. Results: The EQ-5D-5L questionnaire demonstrated high reliability and validity with a Cronbach’s alpha value of 0.737, EQ-5D-5L random forest machine learning regression model RMSE value of 0.1396, and adequate scores from other measures. Lower quality of life was found in patients with multimorbidity who had chronic conditions such as angina pectoris, heart failure, atrial fibrillation, or joint diseases, as well as the patients who were older than 60 years of age, women, or unemployed. Different aspects of quality of life were also significantly negatively impacted by diabetes, asthma, and chronic kidney disease. Heart failure, joint diseases, and older age had the biggest negative effect on quality of life. Conclusions: It is found that the Lithuanian EQ-5D-5L questionnaire is suitable for the assessment of the quality of life in patients with multimorbidity and indicates lower quality of life among those with specific cardiovascular and joint disorder chronic conditions and, in particular, demographic groups.