The biodegradability of both unsaturated (UPEA) and saturated (SPEA) poly(ester-amide)s and a series of hydrogels (UPEA-G) fabricated from UPEA and poly(ethylene glycol) diacrylate (PEG-DA) was examined as a function of PEA chemical structures in both phosphate buffered saline (PBS) and alpha-chymotrypsin solutions. Based on the weight loss data, alpha-chymotrypsin had a much more profound effect on the hydrolyses of UPEA, SPEA polymers (up to 32% weight loss on day 1 for FPBe) and UPEA-G hydrogels (up to 32% weight loss on day 31 for FPBe-G28) than a PBS buffer (less than 10% for polymers and 16% for hydrogels). The changes in elastic moduli and the interior morphology of the hydrogels in both PBS buffer and alpha-chymotrypsin solutions were also monitored for 2 months, and the hydrogels' crosslinking density (n(e)) and molecular weight between crosslinks (M(c)) before and after biodegradation were then examined as a function of biodegradation time, enzyme concentration, and different chemical structure of precursors. The differences in biodegradation rates among PEA polymer and UPEA-G hydrogels are ascribed to differences in hydrophilicity and saturated or unsaturated structure of the polymers and hydrogel precursors. Our results showed that, by changing the concentration of alpha-chymotrypsin, the type of UPEA precursors and their feed ratio, the UPEA-G hydrogels could have controllable biodegradability, which is quite desirable for a wide range of biomedical and pharmaceutical applications.