Abstract Perchlorate (ClO4−) in polar ice preserves past chlorine oxidation chemistry; however, multi‐centennial Antarctic ClO4− records and the mechanisms controlling their variability remain poorly constrained. Here, we present the first 400‐year (1616−2016) ClO4− record from an Antarctic ice core, revealing two regimes separated around 1980. Before 1980, ClO4− variability is primarily controlled by natural drivers. Annual ClO4− deposition fluxes covary with sunspot group number, suggesting UV‐driven modulation of stratospheric chlorine activation. And elevated ClO4− levels follow stratospheric volcanic eruptions, likely reflecting enhanced heterogeneous chlorine activation on stratospheric sulfate aerosols. After 1980, annual ClO4− fluxes increase from 2.4 ± 3.2 g km−2 yr−1 to 5.5 ± 3.2 g km−2 yr−1 and become negatively correlated with Antarctic ozone. This increase coincides with rising anthropogenic chlorine emissions, indicating that anthropogenic chlorine has dominated Antarctic ClO4− production since 1980. These results highlight ClO4− as a proxy for reconstructing stratospheric chlorine chemistry and Antarctic ozone depletion.