Surface Enhanced Raman spectroscopy (SERS) is a molecular‐specific analytical technique with various applications. Although electromagnetic (EM) and chemical (CM) mechanisms have been proposed to be the main origins of SERS, exploring highly sensitive SERS substrates with well‐defined mechanistic pathways remains challenging. Since surface and electronic structures of substrates were crucial for SERS activity, zero‐valent transition metals (Fe and Cu) were intercalated into MoO3 to modulate its surface and electronic structures, leading to unexceptional high enhancement factors (1.0×108 and 1.1×1010 for Fe‐MoO3 and Cu‐MoO3, respectively) with decent reproducibility and stability. Interestingly, different mechanistic pathways (CM and EM) were proposed for Fe‐MoO3 and Cu‐MoO3 according to mechanistic investigations. The different mechanisms of Fe‐MoO3 and Cu‐MoO3 were rationalized by the electronic structures of the intercalated Fe(0) and Cu(0), which modulates the surface and electronic structures of Fe‐MoO3 and Cu‐MoO3 to differentiate their SERS mechanisms. [ABSTRACT FROM AUTHOR]