Background: The coronavirus disease 2019 (COVID-19) pandemic has created challenges that have caused profound changes in health behaviors. This study aimed to explore how COVID-19 is affecting the health-related quality of life (QoL) among Chinese adults. Methods: The data of health-related behaviors and QoL were collected via online surveys from 2289 adults (mean age = 27.8 ± 12 years) who had been isolated at home for an average of 77 days. Results: More than 50% of the respondents reported that their time engaged in daily physical activity (PA) decreased, while sedentary behavior (SB) time increased compared with that before the lockdown. Only 20% of the respondents reported engaging in moderate-to-vigorous PA, 23% of adults reported changed their diets to be healthier, and 30% reported consuming more vegetables, fruits, and milk products than before home-isolation. During home-isolation, 75.2% of the adults rated their sleep quality as very good, and 65% reported that they were satisfied with their QoL. Sleep quality mediated the relationship between PA and QoL. Conclusion: The two-to-three-month home-isolation has had mixed effects on adult health behaviors in China. The participants were found to have focused more on their eating quality and patterns, which had a positive influence on their QoL. However, people should be encouraged to exercise at home with limited space to maintain a generally healthy lifestyle during a prolonged quarantine.