Cross-linking of electrospun (e-spun) fibre mats (beaded fibre morphology with the average diameter of the fibre segments between beads being ~108 nm) of poly(vinyl alcohol) (PVA) containing sodium salicylate (SS), used as the model drug, was achieved by exposing the fibre mats to the vapour from 5.6 M aqueous solution of either glutaraldehyde or glyoxal for various exposure time intervals, followed by a heat treatment in a vacuum oven. With increasing the exposure time in the cross-linking chamber, the morphology of the e-spun fibre mats gradually changed from a porous to dense structure. Both the degree of swelling and the percentage of weight loss of the cross-linked fibre mats (i.e. ~200–530% and ~15–57%, respectively) were lower than those of the untreated ones (i.e. ~610% and ~67%, respectively). Cross-linking was also responsible for the monotonic increase in the storage moduli of the cross-linked SS-loaded e-spun PVA fibre mats with increasing exposure time in the cross-linking chamber. The release characteristic of the model drug from the SS-loaded e-spun PVA fibre mats both before and after cross-linking was assessed by the transdermal diffusion through a pig skin method. The cumulative release of the drug from these matrices could be divided into two stages: 0–4 and 4–72 h, in which the amount of SS released in the first stage increased very rapidly, while it was much slower in the second stage. Cross-linking slowed down the release of SS from the drug-loaded fibre mats appreciably and both the rate of release and the total amount of the drug released were decreasing functions of the exposure time interval in the cross-linking chamber. Lastly, the cross-linked SS-loaded e-spun PVA fibre mats were non-toxic to normal human dermal fibroblasts.