Background: Although COVID-19 has affected over 220 countries by October 2021, there is limited research examining the patterns and determinants of adherence to infection control measures over time. Aims: Our study examines the sociodemographic factors associated with changes in the frequency of adherence to personal hygiene and social distancing behaviors in Hong Kong. Methods: A serial cross-sectional telephone survey in the general population was conducted during the first (March 2020) (n = 765) and third wave (December 2020) (n = 651) of the local outbreak of the COVID-19 pandemic. Respondents were asked about their level of compliance with various personal hygiene and social distancing recommendations. Results: By the third wave, mask use increased to 100%, and throughout the study periods, >90% practiced frequent hand hygiene. However, adherence to social distancing measures significantly waned over time: avoidance of social gatherings (80.5% to 72.0%), avoidance of public places/public transport (53.3% to 26.0%), avoidance of international travel (85.8% to 76.6%) (p < 0.05). The practice of ordering food takeout/home delivery, however, increased, particularly among high-income respondents. Higher education, female gender and employment status were the most consistently associated factors with adherence to COVID-19 preventive practices in the multivariable models. Conclusions: In urban areas of this region, interventions to improve personal hygiene in a prolonged pandemic should target males and those with low education. In addition to these groups, the working population needs to be targeted in order to improve adherence to social distancing guidelines.