Hydrogels composed of hyperbranched poly(amine-ester) (HPAE) macromers with 36% of terminal C=C groups were prepared as a pH-sensitive multi-drug release system with low swelling ratios (4.2% for the lowest one). Anticancer drugs including doxorubicin hydrochloride (Dox), 5-fluorouracil (5FU) and hydroxycamptothecin (HPT) were separately encapsulated in HPAE macromers before hydrogel formation and their release can be controlled by the conformational change of HPAE macromers under different pH conditions, fast when pH > 7 and slow when pH < 7. Furthermore, this system allows a combination release of multiple drugs and the release behavior of each drug was relatively independent with no interference from each other. This is different from traditional pH-sensitive hydrogel systems which control the drug release by a swelling-shrinking mechanism. HPAE hydrogels exhibited pH-controllable drug release properties with a relatively constant volume, because the swelling of hydrogel is limited due to the unique globe like structure of HPAE molecules. These findings show the great promise of HPAE hydrogels as a smart release system for controlled delivery of single or multiple drugs in combined therapy, and where a constant volume of the release system is required.