•Underweight and obese older adults had poorer general health compared to those meeting both physical activity guidelines with normal weight.•Meeting muscle strengthening activities only or meeting neither physical activity guideline were more likely to have poorer physical health regardless of weight status.•Older adults who met neither physical activity guideline had higher odds of poor mental health.•Meeting muscle strengthening activity only or meeting neither PA guideline was associated with more frequent activity limitation days. The purpose of this study was to examine how meeting physical activity (PA) guidelines (i.e., moderate-to-vigorous aerobic activity, muscle strengthening activity) and weight status were interactively related to health-related quality of life (HRQoL) among older adults. A cross-sectional analysis was conducted using data from 87,495 older adults aged 65+ years who participated in the U.S. 2019 Behavioral Risk Factor Surveillance System. PA, weight status, and HRQoL were assessed by validated questionnaires via phone interviews. Binomial logistic regression models were used to examine the interactive effects of meeting PA guidelines and weight status on the odds of having poor HRQoL after controlling for key confounders. Compared to participants meeting both PA guidelines and with normal weight, both underweight and obese older adults had significantly higher odds of having poor general health (OR= 1.55–6.16) regardless of meeting PA guideline status, and those meeting muscle strengthening activities only or meeting neither PA guideline reported higher odds of poor physical health (OR= 1.83–6.22) regardless of weight status. Similarly, those meeting neither PA guideline had significantly higher odds of having poor mental health (OR= 1.69–2.78) regardless of weight status, and those meeting muscle strengthening activities only or meeting neither PA guideline reported higher odds of having frequent activity limitation days (OR= 2.18–7.05). The positive associations between moderate-to-vigorous aerobic PA and HRQoL indicate the need to promote aerobic PA in older adults. Both sex and weight status should be considered when designing PA interventions to improve HRQoL among older adults.