The ring-opening functionalization strategy in tetrahydrofuran (THF) represents an ideal approach to access different valuable structures. Herein, we report different operationally simple, efficient, unique, and practical regioselective heteronucleophilic ring-opening strategies for the THF system. Tf2O, which is a strong electrophilic activator, was found to generate a THF triflate intermediate that triggers the nucleophilicity of nitriles (Nu1) and led to regioselective ring opening in the presence of different nucleophiles (Nu2). Furthermore, the synthesis of different heteronucleophilic ring-opening dimerization products was attributed to the nucleophilicity of Nu2. We also demonstrated that use of borane-tetrahydrofuran (BTHF) can achieve challenging hydride addition in a similar manner.