The use of ligands to control regioselectivity in transition‐metal‐catalyzed CH activation/functionalization is a highly desirable but challenging task. Recently, Itami et al. reported an important finding relating to Pd‐catalyzed ligand‐controlled α/β‐selective CH arylation of thiophenes. Specifically, the use of the 2,2′‐bipyridyl ligand resulted in α‐arylation, whereas the use of the bulky fluorinated phosphine ligand POCH(CF3)23 resulted in β‐arylation. Understanding of this surprising ligand‐controlled α/β‐selectivity could provide important insights into the development of more efficient catalyst systems for selective CH arylation, and so we carried out a detailed computational study on the problem with use of density functional theory methods. Three mechanistic possibilities—SEAr and migration, metalation/deprotonation, and Heck‐type arylation mechanisms—were examined. The results showed that the SEAr and migration mechanism might not be plausible, because the key Wheland intermediates could not be obtained. On the other hand, our study indicated that the metalation/deprotonation and Heck‐type arylation mechanisms were both involved in Itami’s reactions. In the metalation/deprotonation pathway the α‐selective product (C5‐product) was preferred, whereas in the Heck‐type arylation mechanism the β‐selective product (C4‐product) was favored. The ligands played crucial roles in tuning the relative barriers of the two different pathways. In the 2,2′‐bipyridyl‐assisted system, the metalation/deprotonation pathway was energetically advantageous, leading to α‐selectivity. In the POCH(CF3)23‐assisted system, on the other hand, the Heck‐type arylation mechanism was kinetically favored, leading to β‐selectivity. An interesting finding was that POCH(CF3)23 could produce a CH⋅⋅⋅O hydrogen bond in the catalyst system, which was crucial for stabilization of the Heck‐type transition state. In comparison, this CH⋅⋅⋅O hydrogen bond was absent with the other phosphine ligands i.e., P(OMe)3, PPh3, PCy3 and these phosphine ligands therefore favored the metalation/deprotonation pathway leading to α‐selectivity. Furthermore, in this study we have provided theoretical evidence showing that the Heck‐type arylation reaction could proceed through an anti‐β‐hydride elimination process. Switching regioselectivity: Pd‐catalyzed ligand‐controlled α/β‐selective CH arylation of thiophenes was studied computationally: metalation/deprotonation and Heck‐type arylation mechanisms were found to be involved (see figure). The ligands played a crucial role in tuning the relative barriers of the two pathways. Interestingly, POCH(CF3)23 could produce a CH⋅⋅⋅O hydrogen bond, crucial for stabilization of the Heck‐type transition state.