Sonodynamic therapy (SDT) is garnering considerable attention in cancer treatment due to its non‐invasive nature and the potential of spatiotemporal control. However, the high level of glutathione (GSH) in cancer cells can alleviate the SDT‐mediated ROS‐damages, resulting in a reduced SDT effect. Here, a two‐in‐one nano‐prodrug for photoacoustic imaging‐guided enhanced SDT against skin cancers is synthesized. A dual‐prodrug molecule (DOA) of sulfide dioxide (SO2) and 5‐aminolevulinic acid (ALA) is first synthesized and then co‐assembled with methoxyl poly(ethylene glycol)‐b‐poly(l‐lysine) (mPEG‐b‐PLL) to generate the two‐in‐one prodrug nanoparticles (P‐DOA NPs). The P‐DOA NPs simultaneously released ALA and SO2 in response to the overexpressed GSH in tumor cells. The released ALA is metabolically converted into protoporphyrin IX (PpIX) in tumor cells for SDT and photoacoustic imaging. Meanwhile, the released SO2, together with the consumption of GSH based on the reaction of DOA in P‐DOA NPs with intracellular GSH, can significantly increase the intracellular ROS content, leading to enhanced SDT. As a result, the P‐DOA NPs significantly inhibited the growth of melanoma and squamous cell carcinoma xenografts in mouse models under the guidance of real‐time photoacoustic imaging. Therefore, this novel two‐in‐one nano‐prodrug is promising for effective SDT against skin cancers.