In 1917, Constantine I insisted that Greece remain neutral in World War I, while Prime Minister Eleftherios Venizelos was determined to go to war in support of the Triple Entente. At Venizelos' invitation, French and British troops entered Greece and forced Constantine I and his first born son Crown Prince George into exile (National Schism). Young Alexander, a proponent of the Megali Idea, was enthroned as King; in reality he had absolutely no power and was a rubber stamp for the Prime Minister, and his only real task was to visit the front frequently and rally the troops.

On one major issue, however, he did defy Venizelos: on 4 November 1919 he eloped with Aspasia Manos (1896 – 1972), a commoner, daughter of Colonel Petros Manos, causing a scandal and infuriating Venizelos. Aspasia was forced to flee Athens until the crisis was resolved and the wedding was legalized without Aspasia being recognised as Queen, but merely as "Madame Manos". Six months later, the young couple left for Paris, on condition that they neither travel nor appear at official functions together.

Soon after, the Treaty of Sèvres was signed in August 1920. The Treaty was extremely favourable to Greece giving her large territories in Thrace and around Smyrna in modern day Turkey. Alexander became King of a much enlarged Greek state.

Although history has unfairly described King Alexander as a careless pet owner who died from a bite "from his pet monkey"; the 27 year old monarch actually died after defending his pet dog from an attack during a walk through the Royal Gardens, and he suffered wounds from two of the monkeys. The attack occurred on 2 October 1920. In the report dispatched from Europe, it was stated that the King had been walking in the park with a pet dog, when the dog was attacked by a monkey. The King fended off the monkey with a stick but in the fight the monkey bit him on the hand slightly. "Another monkey rushed to the defense of his mate, and in fending it off, the King received another bite which severely lacerated a gland. The infection which set in following the bites gradually poisoned the King's entire system ..." Both animals were found to have been diseased after they were destroyed. Within days, he developed a severe reaction to the infection, and after initial signs of improvement, became critically ill on 12 October. It is little reported but nonetheless extremely likely that the infection was caused by Monkey B virus which causes a fatal ascending myelitis in man and unremarkable oral lesions in a monkey. There is a relation to Herpes.

On 25 October 1920 King Alexander died at Athens, of sepsis. His father Constantine I was permitted to return to Greece as King. Eventually, King Constantine would lead the Greeks to engage in the Greco - Turkish War which resulted in Greece's defeat, a quarter of a million military and civilian casualties and the end of the Megali Idea. Winston Churchill would later write that "it was a monkey bite that caused the death of those 250,000 people." The territory gained on the Turkish mainland during Alexander’s reign was lost.

King Alexander's only child, born after his death, was Princess Alexandra of Greece (1921 – 1993), who later married Peter II, King of Yugoslavia. Her mother, Madame Manos, was granted the style "Princess Alexander" by the restored King Constantine.

The city of Alexandroupolis (formerly Dedeagatch), near the river Evros on the Greco - Turkish border, was renamed after him in 1920 on the occasion of his visit there. He was the first King of Greece to visit the city since its capture by the Hellenic Army during World War I, and the official change of guard between Bulgarian and Greek officials on 14 May 1920.

Alexander is unusual among monarchs as he ruled in exception to standard primogeniture tradition. He assumed the throne upon the abdication of his father, though his older brother George still lived. In addition, his older brother would later become King of the Hellenes in his own right, providing a rare case where an older brother would succeed a younger one to the throne (though in this case not directly).