Small molecules that can alter the activity of the LINE1 endonuclease, an enzyme involved in retrotransposition of transposable elements in the human genome, were identified through in vitro, in silico, and biochemical screening. The LINE1 endonuclease induces double-stranded breaks in DNA beyond retrotransposition events, suggesting its activity contributes significantly to genetic instability. A subset of small molecules were found to minimize the activity of LINE1 endonuclease and therefore show promise for limiting LINE1-induced genetic instability.