As scaling down to the nanoscale, the dramatically increased morphological deviation between nanostructures becomes a major challenge in implementing large‐scale nanodevices. On the other side of the coin, the often‐undesirable rich non‐repeatable randomness introduced during nanostructure growth and subsequent device fabrication is of great value in the implementation of physically unclonable functions (PUF), a booming innovative security primitive. Herein, it is shown that the self‐oriented organic nanowires grown on a faceted surface through a vapor transport process are advanced building blocks for the implementation of two novel PUFs. An optical PUF is first demonstrated by exploiting the unclonable morphological randomness of the self‐oriented nanowires (e.g., length, thickness, density, and location), which can provide an entity‐specific primary encryption for nanowire devices. Next, these nanowires are integrated into photodetector arrays directly on their growth substrate and accordingly enable an electrical PUF based on the inherent resistance variation between detector cells. Furthermore, by combining these two PUFs, a secondary encryption with higher security is proposed for information communication. The implementation of nanowire‐based PUFs not only opens a new device direction to exploit the annoying unclonable randomness of bottom‐up nanowires, but also provides innovative label‐free security primitives for emerging nanowire‐based devices and systems.