Abstract This study examined the interrelated effect of environmental pH, gelatin backbone modification and crosslinking modality on hydrogel morphology, surface hydrophilicity, in vitro swelling/degradation kinetics, in vitro drug release kinetics and in vivo degradation, inflammatory response and drug release activity. The percent glutaraldehyde fixation had a greater impact on the morphology of the dehydrated hydrogels than gelatin modification. Any decrease in percent glutaraldehyde fixation and/or modification of gelatin with polyethylene glycol dialdehyde (PEG-dial) and/or ethylenediaminetetraacetic dianhydride (EDTAD) increased hydrogel surface hydrophilicity. Swelling/degradation studies showed that modification of gelatin with PEG-dial generally increased the time to reach the maximum swelling weight ratio ( T max) and the time to failure by hydrolysis ( T fail), but had little effect on the maximum swelling weight ratio ( R max) and the weight ratio at failure ( R fail). Modification of gelatin with EDTAD generally had no effect on T max and T fail, but increased R max and R fail. Modification of gelatin with PEG-dial and EDTAD increased R max, but had no effect on T max, R fail, or T fail. Decreasing percent glutaraldehyde fixation generally increased R max and R fail but decreased T max and T fail. Decreasing environmental pH from 7.4 to 4.5 had no effect on any swelling/degradation properties. In vitro drug release studies showed that modification of gelatin with PEG-dial and/or EDTAD generally decreased the maximum mass ratio of drug released ( D max) and the time to reach D max ( T dmax). Percent glutaraldehyde fixation did not significantly affect D max or T dmax (except for EDTAD-modified gelatin hydrogels). In vivo studies showed that gelatin-based hydrogels elicited comparable levels of acute and chronic inflammatory response as that of the empty cage control by 21 d.