Objective: To investigate the status and influencing factors of quality of life (QoL) among young and middle-aged patients with pulmonary tuberculosis (PTB) and their spouses, thereby providing evidence-based guidance for targeted interventions to improve their QoL. Methods: From September to November 2023, a stratified cluster sampling method was employed to conduct a questionnaire-based survey among hospitalized young and middle-aged PTB patients and their spouses at two tuberculosis (TB) designated hospitals in Guangdong Province, including 60 patient-spouse pairs at the First Navy Hospital of Southern Theater Command and 60 patient-spouse pairs at Central People's Hospital of Zhanjiang. A total of 240 pieces of questionnaire were distributed (120 for patients and 120 for spouses). Missing data were handled via listwise deletion, excluding responses with missing values in key variables (Generic Quality of Life Inventory-74 (GQOLI-74) scores and core demographic characteristics). Ultimately, 221 valid responses were collected (112 from patients and 109 from spouses), yielding a response rate of 92.08%. The survey included a self-developed general information questionnaire and the GQOLI-74. The general information questionnaire for patients covered the following aspects: (1) Sociodemographic Characteristics: Age, sex, educational level, local household registration status, employment status, household income, per capita living space; (2) QoL Parameters: Marital relationship, sexual life; (3) Clinical Data: Treatment category, diagnostic category, presence of complications, disease duration, adverse reactions to anti-TB medications, smoking status, body mass index (BMI), sleep quality, treatment adherence, current treatment phase, and disease severity; (4) Exposure to TB-related health education. The spouse questionnaire included five aspects: (1) Sociodemographic Characteristics: Age, sex, educational level, local household registration status, employment status, household income, per capita living space; (2) Patient Clinical Data: Patient's treatment category, diagnostic category, presence of complications, and disease duration; (3) QoL Parameters: Marital relationship, sexual life; (4) Health Status: Smoking status, BMI, sleep quality, presence of chronic illnesses; (5) Exposure to TB-related health education and level of knowledge regarding TB prevention and control. Univariable and multivariable linear regression models were employed to analyze the QoL status and its influencing factors among both patients and their spouses. Results: According to GQOLI-74, the average overall QoL score for spouses was 57.74±8.01, significantly higher than that of the patients (50.56±6.05, t=4.550, P<0.001). In the domains of social and physical functioning, spouses also scored significantly higher than patients (62.86±10.63 vs. 52.91±12.31, t=3.317, P<0.001; and 62.95±12.90 vs. 55.06±14.27,t=2.257, P=0.026). In contrast, differences in material life (37.39±13.63 for patients vs. 43.39±18.28 for spouses) and psychological functioning (56.88±11.45 for patients vs. 61.74±11.75 for spouses) were not statistically significant (t=1.683, P=0.095; t=1.704, P=0.091). Multiple linear regression analysis identified household income, sexual life, marital relationship, and TB-related health education as independent predictors of QoL in both patients (β=3.104,P<0.001;β=2.625,P=0.012;β=2.657,P=0.003;β=3.758,P=0.001) and their spouses (β=4.407,P<0.001;β=4.836,P<0.001;β=2.286,P=0.038;β=5.319,P=0.002). In addition, adverse drug reactions (β=-2.344, P=0.005) and treatment adherence (β=1.582, P=0.010) were independent factors influencing patients' QoL. For spouses, awareness of TB prevention and control knowledge was an independent predictor (β=3.807, P<0.001). Conclusion: This study confirms that PTB significantly compromises the QoL of both young and middle-aged patients and their spouses, influenced by a combination of clinical, psychosocial, and educational factors. The findings provide empirical support for family-centered, targeted interventions aimed at improving QoL among affected households.