A test-negative case-control study was conducted to assess inactivated influenza vaccine effectiveness (VE) in children aged 6 months-17 years. The database was developed from the US Department of Defense Global Respiratory Pathogen Surveillance Program over four consecutive influenza seasons from 2016 to 2020. A total of 9,385 children including 4,063 medically attended, laboratory-confirmed influenza-positive cases were identified for VE analysis. A generalized linear mixed model with logit link and binomial distribution was used to estimate the VE. The adjusted VE for children was 42% [95% confidence interval (CI): 37-47%] overall, including 55% (95% CI: 47-61%) for influenza A(H1N1)pdm09, 37% (95% CI: 28-45%) for influenza A(H3N2), and 49% (95% CI: 41-55%) for influenza B. The analysis by age groups indicated that the adjusted VE in children aged 6 months-4 years was higher against influenza A(H1N1)pdm09 and influenza B, and comparable against influenza A(H3N2), compared to those in children aged 5-17 years. Further age-stratified analysis showed that the VE against any types of influenza was low and non-significant for children aged 6-11 months (33%; 95% CI:-2-56%), but it was high (54%; 95% CI: 34-67%) in children aged 12-23 months, and then declined linearly with increasing age. In conclusion, the inactivated influenza vaccination was moderately effective against influenza infection, based on the analysis from a large number of children aged 6 months-17 years over multiple influenza seasons.