BACKGROUND Filling a prescription on the web has become an alternative to in-person pharmacies for individuals to access their medications. However, the adoption of web-based filling has been gradual, and the use patterns remain to be unclear. OBJECTIVE This study aims to estimate the trend and prevalence of web-based prescription-filling behavior and identify associated factors among adults in the United States. METHODS We used data from the US National Health Interview Survey (NHIS) from 2009 to 2018. Adult respondents (aged ≥18 years and over) self-reported their behavior of web-based prescription filling, which was defined as having filled a prescription using the internet in the past 12 months during the survey year. We reported trends using weighted percentages adjusted by the NHIS complex sampling design. We used descriptive statistics and multivariable logistic regression models to examine trends and identify factors associated with web-based prescription-filling behavior. RESULTS The estimated number of adults reporting web-based prescription-filling behavior significantly increased from 13,319,877 (13,319,877/225,217,942, 5.91%) in 2009 to 28,308,262 (28,308,262/246,611,125, 11.48%) in 2018 <i>(P</i>&lt;.001). Those who were more likely to report filling a prescription on the web were aged between 35 and 74 years, female, White, and frequent users of the computer or internet; these adults also reported higher education, higher income, insurance coverage, and poorer health status. CONCLUSIONS Web-based prescription-filling behavior among US adults has increased significantly from 2009 to 2018. Health care providers should be aware of the upward trend in the use of web-based pharmacies and ensure the clinical safety of web-based prescriptions.