Associations of physical function and health-related quality of life in 297 rural women, ages 40–69 years (body mass index of 28–45 kg/m2) who met activity criterion were examined using cross-sectional baseline data from the Women Weigh-in for Wellness trial (ClinicalTrials.gov NCT01307644). Assessments included demographics, 400-m walk, timed chair stands, and health-related quality of life using the Patient-Reported Outcomes Measurement Information System (PROMIS-29). Women were classified as active if they had ≥500 metabolic equivalent·min/week by the Behavioral Risk Factor Surveillance System survey (n = 103, 34.7%), or ≥150 weekly minutes of greater than or equal to moderate intensity activity by accelerometry (n = 222, 74.8%). Ordinal logistic regression models adjusted for age, comorbidities, and body mass index were calculated. Meeting activity guidelines per self-report was associated with perceptions of less fatigue and greater satisfaction with social roles, whereas meeting guidelines as measured by accelerometry was associated with faster gait speed.