The micro-mechanical properties of 5 μm thick histological sections of ferret aorta and vena cava were mapped as a function of distance from the outer adventitial layer using nanoindentation. In order to decouple the effect of the glass substrate on the elastic modulus of these thin sections, the nanoindentation data were analyzed using the extended Oliver and Pharr method which is readily accessible for coatings and layered materials with the software package, FilmDoctor®. In the aorta, the elastic modulus was found to decrease progressively from 35 MPa at the adventitia (outermost layer) to 8 MPa at the intima (innermost layer). This decrease in modulus was inversely correlated with elastic fibre density. In contrast, in the vena cava, the stiffest regions were found to be the adventitial (outer) and intimal (innermost) sections of the vessel cross-section. Both these regions were enriched in ECM components. The central region, thought to be largely cellular, had a relatively constant modulus of around 20 MPa. This study demonstrates that with this methodology it is possible to distinguish micro-mechanically between large arteries and veins, and therefore the same approach should allow age or disease related changes in the mechanical properties within a tissue to be quantified.