Retrotransposition of long interspersed nuclear element-1 (LINE-1) drives genomic instability, thereby contributing to congenital malformations and aging. While the transcriptional control of LINE-1 is well-documented, the post-translational regulation of its protein products remains poorly understood. Here we show that the E3 ubiquitin ligase TRIM25 interacts with ORF1p and promotes its degradation through ubiquitination. Exploiting this mechanism and guided by molecular dynamics simulations, we identified a small-molecule compound that cooperatively stabilizes the TRIM25-ORF1p interaction to accelerate target degradation. Given that age-related LINE-1 activation in germ cells contributes to de novo mutations and reproductive risks in older parents, our findings demonstrate a targeted pharmacological approach to downregulate ORF1p. This study provides a framework for mitigating age-associated genomic instability by modulating LINE-1 protein levels.