ABSTRACTMultifunctional electrospun scaffolds were prepared from two polylactide (PLA) grades having slightly different d‐lactide content (4.2 wt % and 2.0 wt %). Triclosan (TCS), ketoprofen (KTP), and p‐coumaric acid (CUM) were selected as bactericide, anti‐inflammatory, and antioxidant agents, respectively. Single, binary, and ternary drug‐loaded microfibers having a unimodal diameter distribution could be prepared using a common chloroform:acetone:dimethylsulfoxide mixture and similar operational parameters (i.e., voltage, flow rate, and tip–collector distance). FTIR spectra were sensitive to the low amount of drugs loaded and even showed slight differences in PLA conformation. DSC heating scans clearly demonstrated the ability of electrospinning to induce molecular orientation of PLA and also the nucleation effect of incorporated drugs to induce crystallization. Thus, crystallinity of binary drug‐loaded scaffolds was significantly higher than observed for unloaded samples. Release behavior of the three drugs from loaded scaffolds and PLA matrices in PBS:ethanol medium was evaluated. A rapid release was always detected, together with partial drug retention which was higher when the more stereoregular PLA matrix was employed. A strong bactericidal effect was found when scaffolds were loaded with 3 wt/vol % of TCS, but incorporation of a small percentage of KTP (i.e., 1 wt/vol %) had a bacteriostatic effect even in the absence of TCS. The inherent cytotoxicity of TCS could be well neutralized by enhancing cell viability by incorporation of CUM and/or KTP. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 42751.