This paper reports a drug-loaded three-phase microbubble fabrication method using a simple three-dimensional microfluidic chip. The three-dimensional microfluidic chip has a simple design of the nozzle using multilayer exposure technique, so that it has much lower manufacture cost, and it can still generate microbubbles with a small size. Microbubbles made by this chip have uniform size and low diameter, which could be controlled under 5 μm. We not only reduced microbubble’s size greatly, but also got stabilized a higher yield of microbubbles with a high yield. We generated stabilized doxorubicin-loaded microbubbles with a phospholipid shell by adjusting oil phase formula. The microbubbles could stay more than half a month. The effects on doxorubicin payload, encapsulation efficiency and in vitro enhancement were explored as well.