DNA origami is a powerful method for the creation of 3D nanoscale objects, and in the past few years, interest in wireframe origami designs has increased due to their potential for biomedical applications. In DNA wireframe designs, the construction material is double stranded DNA, which has a persistence length of around 50 nm. In this work, we study the effect of various design choices on the stiffness versus final size of nanoscale wireframe rods, given the constraints on origami designs set by the DNA origami scaffold size. An initial theoretical analysis predicts two competing mechanisms limiting rod stiffness, whose balancing results in an optimal edge length. For small edge lengths, the bending of the rod’s overall frame geometry is the dominant factor, while the flexibility of individual DNA edges has a greater contribution at larger edge lengths. We evaluate our design choices through simulations and experiments and find that the stiffness of the structures increases with the number of sides in the cross section polygon, and that there are indications of an optimal member edge length. We also ascertain the effect of nicked DNA edges on the stiffness of the wireframe rods and demonstrate that ligation of the staple breakpoint nicks reduces the observed flexibility. Our simulations also indicate that the persistence length of wireframe DNA structures significantly decreases with increasing monovalent salt concentration.