Twisted van der Waals multilayers are widely regarded as a rich platform to access novel electronic phases thanks to the multiple degrees of freedom available for controlling their electronic and chemical properties. Here, we propose that the stacking domains that form naturally due to the relative twist between successive layers act as an additional ”knob” for controlling the behavior of these systems and report the emergence and engineering of stacking domain-dependent surface chemistry in twisted few-layer graphene. Using mid-infrared near-field optical microscopy and atomic force microscopy, we observe a selective adhesion of metallic nanoparticles and liquid water at the domains with rhombohedral stacking configurations of minimally twisted double bi- and trilayer graphene. Furthermore, we demonstrate that the manipulation of nanoparticles located at certain stacking domains can locally reconfigure the moiré superlattice in their vicinity at the micrometer scale. Our findings establish a new approach to controlling moiré-assisted chemistry and nanoengineering. © 2023 American Chemical Society