The event that marked the beginning of a significant U.S. foreign policy shift towards isolationism post-WWI was the signing of the Treaty of Versailles in 1919 and the subsequent widespread disillusionment with foreign entanglements. The U.S. Senate's rejection of the Treaty reflected a desire to avoid future involvement in European conflicts. This isolationist sentiment was compounded by the domestic challenges of the 1920s and the Great Depression in the 1930s, leading to policies that prioritized national interests over international commitments and a reluctance to engage in international alliances or conflicts until World War II.