In this study, we provide the first evidence that isobutyrylshikonin and α-methylbutyrylshikonin, two naphthoquinones extracted from the roots of Onosma visianii, induce strong apoptotic, antiproliferative, and STAT3-dependent cytotoxic effects in mouse CLL cells, BCL1, and human B-PLL cells, JVM-13, with significant in vivo antitumor effects. This evidence concerns the gene STAT3 and B-cell chronic lymphocytic leukemia.