Background: Although considered one of the most important prognostic factors for lung cancer patients, the health-related quality of life (HRQOL) of the newly diagnosed lung cancer population remains scarcely focused on in the literature. Therefore, we aimed to identify the determinants of HRQOL among newly diagnosed lung cancer patients in Taiwan. Methods: Two hundred and fifty patients newly diagnosed with lung cancer were recruited from a medical center in northern Taiwan through convenience sampling. Four structured questionnaires, including the Taiwanese version of the MD Anderson symptom inventory (MDASI-T), the Taiwanese version of the Pittsburgh Sleep Quality Index (PSQI-T), the International Physical Activity Questionnaire-Short Form (IPAQ-SF), and the World Health Organization Quality of Life-BREF (WHOQOL-BREF), were used to collect data. Further, a multivariate stepwise linear regression was conducted to determine the independent risk factors for HRQOL. A p value of less than 0.05 was considered statistically significant. Results: The patients (mean age was 61.04 years, 51.2% male, 94.0% non-small-cell lung cancer, 56.4% stage IIIB-IV) had moderate levels of HRQOL among the physical, psychological, social, and environmental domains, as well as overall QOL. HRQOL was not correlated with married status, religion, and comorbidity. Gender, age, family income, smoking status, cancer stage, ECOG PS scores, PA, symptom burden (severity and interference), and PSQI global scores were correlated with HRQOL. Notably, symptom severity was the dominant negative predictor affecting the psychological and environmental domains of QOL (β = -4.313 and -3.500, respectively), accounting for 23.2% and 14.6% of the variance, respectively. On the other hand, symptom interference was the dominant negative predictor affecting the physical and social domains of QOL, as well as overall QOL (β = -3.592, -1.984, and -0.150, respectively), accounting for 44.4%, 15.0%, and 24.1% of the variance, respectively. Conclusion: Newly diagnosed lung cancer patients suffered symptom severity and interference that significantly impaired their HRQOL; particularly, symptom interference affected the physical domain of QOL. Healthcare professionals should pay more attention to cancer-related symptom severity, symptom interference, and HRQOL changes when caring for newly diagnosed lung cancer patients.