Microbubbles (MBs) are increasingly being proposed as delivery vehicles for targeted therapeutics, as well as being contrast agents for ultrasound imaging. MBs formed with a lipid shell are promising candidates due to their biocompatibility and the opportunity for surface functionalization, both for specific targeting of tissues and as a means to tune their mechanical response for localized ultrasound induced destruction in vivo. Herein, we acquired force-deformation data on coated lipid MBs using tip-less microcantilevers in an atomic force microscope. Model lipid MBs were designed to test the effects of adding a functional coating on the outside of the lipid leaflet, including a protein coat (streptavidin) or the addition of quantum dots (Q-dots) as optical reporters. MBs (~3 μm diameter) were repeatedly compressed for deformations up to ~50% to obtain a full bubble response. Addition of a coating increased the initial deformation stiffness related to shell bending ~2-fold for streptavidin and ∼3-fold for Q-dots. The presence of a polyethylene glycol (PEG) linker in between the lipid and functional coating, led to enhanced stiffening at high deformations. The plasticity index has been determined and only those MBs that included the PEG linker showed a force dependent short time-scale (<~1s) plasticity. This study demonstrates modulation of the mechanical response of biocompatible MBs through the addition of functional coatings necessary for rationale design of therapeutic lipid MBs for targeted drug delivery.