William Jennings Bryan's resignation as Secretary of State was a significant moment in U.S. political history, reflecting the contentious atmosphere surrounding American foreign policy during World War I. Bryan, a three-time presidential candidate known for his progressive ideals, joined Wilson's cabinet in 1913. However, as the war escalated, his commitment to a neutral stance became increasingly at odds with Wilson's administration, which debated how to respond to German aggression and submarine warfare.

The major catalyst for Bryan's resignation was the tragic sinking of the RMS Lusitania in May 1915, where a German U-boat torpedoed the British ocean liner, resulting in the deaths of 1,198 passengers, including 128 Americans. This event sparked outrage in the United States and increased calls for intervention in the war. Wilson, seeking to maintain neutrality while appeasing public sentiment, was preparing a diplomatic response that Bryan felt was too harsh and could jeopardize peace efforts. Bryan believed that the U.S. response should be more conciliatory, aiming to avoid escalation into war.

The resignation occurred after Bryan presented a statement that condemned Germany's actions while advocating for the principle of neutrality. Wilson's administration, however, leaned towards a more assertive stance. Bryan's departure served as a profound indication of internal conflicts within the government regarding its approach to the war and ultimately underscored the broader national debate over U.S. involvement in World War I.