Purpose: This study aimed to develop and test a structural equation model of health-related quality of life among older women following bilateral total knee replacement based on a literature review and Wilson and Cleary’s model of health-related quality of life. Methods: One hundred ninety three women who were diagnosed with osteoarthritis, were older than 65 years, and were between 13 weeks and 12 months of having a bilateral total knee replacement were recruited from an outpatient clinic. Data were collected from July 2017 to April 2018 using a structured questionnaire and medical records. Data were analyzed using SPSS/WIN 22.0, AMOS 22.0, and Smart PLS 3.2.4. Results: The fitness of the hypothetical model was good, with coefficients of determination (R2) ranging between .28 and .75 and predictive relevance (Q2) between .26 and .73. The standardized root mean square residual of the model fit indices for the hypothetical model was .04; which explained 64.2% of physical and 62.5% of mental health-related quality of life. Self-efficacy, symptom status, functional status, and general health perceptions had a significant direct effect on physical health-related quality of life, while social support, symptom status, and general health perceptions had a significant direct effect on participants’ mental-health-related quality of life. Conclusion: To improve the physical and mental quality of life of older women who receive bilateral knee replacement, nursing-based intervention strategies that reduce symptoms, improve functional status, and increase health perceptions, self-efficacy, and social support are needed. The most important factor is the symptom status.