The three tandem A domains (A1, A2, and A3) of von Willebrand factor (VWF) play critical roles for its functions. The A1 and A3 domains contain respective binding sites for platelet glycoprotein Ib (GPIb) and collagen. The A2 domain hosts a proteolytic site for the VWF-cleavage enzyme A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motifs 13 (ADAMTS-13). Previous studies suggested that shear flow assists the ADAMTS-13 cleavage of VWF by unfolding the A2 domain and thus exposing the cryptic proteolytic site. Here we used steered molecular dynamics (SMD) to simulate the unfolding of the A1 and A2 domains by tensile force. The forced unfolding of A2 started from the C-terminus because of its specific topology. The β-strands of A2 were pulled out sequentially, generating sawtooth-like peaks in the force-extension curves. The disulfide bond between A1 N- and C-termini prevented it from unfolding. After eliminating the disulfide bond, A1 was unfolded similarly as A2 in terms of the β-strand pullouts, but differed in the unfolding of helices. The major resistance of A1 and A2 to unfolding came from the hydrogen bond networks of the central β-sheets. Two different unfolding pathways of the β-strands were observed, where the sliding pathway encountered much higher energy barrier than the unzipping pathway.