Amphetamine (AA) is used in some therapeutic treatments, but it is also one of the most widely used illicit drugs. Therefore, a correct tracking of AA in various environments is crucial for its controlled distribution even inside the human body. However, current sensors are still too large to fit inside the human body and their biocompatibility is still deficient. Since the discovery of nanostructures, especially silicon nanowires (SiNWs), the possibilities of sensors inside the human body have increased due to their enhanced properties and biocompatibility. However, theoretical studies about the capabilities of SiNWs with surface modifications as sensing materials are still scarce. Using Density Functional Theory, we investigate the effects of amphetamine adsorption on the work function, and other electronic and structural properties, of pristine and modified SiNWs. Two types of modifications were studied, i.e., substitutional doping with B, Al, and Ga atoms and surface functionalization with the same species. The adsorption energies of the amphetamine molecule are larger for the doped nanowires, followed by the functionalized ones, and lastly, the undoped Si nanowire.This study shows that undoped, doped, and functionalized SiNWs are excellent candidates for AA sensing, with B being the best chemical species for improving AA adsorption for both doped and functionalized schemes.