Commonly used antihistamines and other cationic amphiphilic drugs (CADs) are emerging as putative cancer drugs. Their unique chemical structure enables CADs to accumulate rapidly inside lysosomes, where they increase lysosomal pH, alter lysosomal lipid metabolism, and eventually cause lysosomal membrane permeabilization. Here, we show that CAD-induced rapid elevation in lysosomal pH is caused by a lysosomal H⁺ efflux that requires P2RX4-mediated lysosomal Ca²⁺ release and precedes the lysosomal membrane permeabilization. The subsequent cytosolic acidification triggers the dephosphorylation, lysosomal translocation, and inactivation of the oncogenic signal transducer and activator of transcription 3 (STAT3) transcription factor. Moreover, CAD-induced lysosomal H⁺ efflux sensitizes cancer cells to apoptosis induced by STAT3 inhibition and acts synergistically with STAT3 inhibition in restricting the tumor growth of A549 non-small cell lung carcinoma xenografts. These findings identify lysosomal H⁺ efflux and STAT3 inhibition as anticancer mechanisms of CADs and reinforce the repurposing of safe and inexpensive CADs as cancer drugs with a drug combination strategy.