Born in Ithaca, Metaxas was a career military officer, first seeing action in the Greco-Turkish War of 1897. Following studies in the German Empire, he returned to join the General Staff and was part of the modernizing process of the Greek Army before the Balkan Wars (1912 – 1913), in which he actively participated. He was appointed as Chief of the Greek General Staff in 1913 and was promoted to Lieutenant General in 1916.

A staunch monarchist, he supported Constantine I and opposed Greek entry into World War I. Eleftherios Venizelos, the prime minister, resigned over the refusal of Metaxas to aid the Allies' unsuccessful Dardanelles campaign and used the war as the major issue in the elections. When Venizelos won the May 1915 elections, he mobilised the army to aid Serbia, but was dismissed by the king. This dismissal solidified the rift between monarchists and Venizelists, creating the "National Schism" that would plague Greek politics for decades. In August 1916, Venizelist officers launched a revolt in Greece's northern city of Thessaloniki, which resulted in the establishment of a separate "Government of National Defence" under Venizelos. The new government, with the Allies' support, expanded its control over half the country, and entered the war on the Allies' side. In June 1917, with Allied support, King Constantine was deposed and Venizelos came to power, declaring war on behalf of the whole country on 29 June 1917.

Metaxas followed the king into exile in Corsica, neither returning until 1920 and the electoral defeat of Eleftherios Venizelos. Metaxas was one of the few who publicly opposed the ongoing Asia Minor Campaign, citing military considerations, and refused to assume any military office in the war. Following the defeat of Greek forces in Asia Minor, King Constantine was again forced into exile by a revolution led by Colonel Nikolaos Plastiras. Metaxas moved into politics and founded the Freethinkers' Party on 12 October 1922. However, his association with the failed royalist Leonardopoulos-Gargalidis coup attempt in October 1923 forced him to flee the country. Soon after, King George II was also forced to follow in exile. The monarchy was finally abolished, and the Second Hellenic Republic proclaimed, in March 1924.

Metaxas returned to Greece soon after, publicly stating his acceptance of the regime change. Despite being one of the most prominent royalist politicians, and a promising start, Metaxas' foray into politics was not very successful. In the 1926 elections, his Freethinkers' Party could claim 15.78% of the vote and 52 seats in Parliament, putting it almost on a par with the other main royalist party, the People's Party. As a result, he became Communications Minister in the "ecumenical government" formed under Alexandros Zaimis. However, infighting within the party and the departure of many members plunged the party to 5.3% and a single seat in the 1928 elections. The 1932 and 1933 elections saw the percentage drop to 1.59%, although the party still returned three MPs, and Metaxas became Interior Minister in the Panagis Tsaldaris cabinet. In the 1935 elections, he cooperated in a union with other small royalist parties, returning 7 MPs, repeating the performance in the 1936.

After a disputed plebiscite George II, son of Constantine I, returned to take the throne in 1935. The elections of 1936 produced a deadlock between Panagis Tsaldaris and Themistoklis Sophoulis. The political situation was further polarized by the gains made by the Communist Party of Greece (KKE). Disliking the Communists and fearing a coup, George II appointed Metaxas, then minister of war, to be interim prime minister on 13 April 1936, and the appointment was confirmed by the Greek parliament.

Widespread industrial unrest in May allowed Metaxas to declare a state of emergency. He suspended the parliament indefinitely and suspended various articles of the constitution. On August 4, 1936 Metaxas declared the 4th of August Regime. The regime's propaganda presented Metaxas as "the First Peasant", "the First Worker" and "the National Father" of the Greeks. Metaxas adopted the title of Arkhigos, Greek for "leader" or "chieftain", and claimed a "Third Hellenic Civilization", following ancient Greece and the Greek Byzantine Empire of the Middle Ages. Patterning his regime on other authoritarian European governments (most notably Italian dictator Benito Mussolini's fascist regime), Metaxas banned political parties, prohibited strikes and introduced widespread censorship of the media. In a short period, his able Security minister, Konstantinos Maniadakis, was able to infiltrate and practically dissolve the Communist Party of Greece.

Trying to build a corporatist state and secure popular support, Metaxas adopted or adapted many of fascist Italy's institutions: a national Labour Service was formed, the 8-hour working day and mandatory improvements to the working conditions of workers were introduced, as was the Social Insurance Institute (IKA), still the biggest social security institution in Greece. In terms of symbolism, the Roman salute was introduced, and the Minoan double-axe, the labrys, made into the Greek equivalent of the fasces. Unlike Mussolini and other dictatorial regimes, however, Metaxas lacked the support provided by a political mass party. The regime's only mass organisation was the National Organisation of Youth (EON). Throughout his rule, Metaxas' power rested primarily upon the army and the support of King George II.

In foreign policy Metaxas followed a neutral stance, trying to balance between the UK and Germany. In the late 1930s, as with the other Balkan countries, Germany became Greece's largest trading partner. Metaxas himself had a reputation as a Germanophile dating back to his studies in Germany and his role in the National Schism; King George however and most of the country's elites were staunchly anglophile, and the predominance of the British Royal Navy in the Mediterranean could not be ignored by a maritime country like Greece. Furthermore, the expansionist goals of Mussolini's Italy drove Greece to lean towards the Franco-British alliance.

The policy of Metaxas to keep Greece out of World War II was decisively broken by the blunt demands of Mussolini on 28 October 1940. He demanded occupation rights to strategic Greek sites and was met with a curt reply by Metaxas: "Alors, c'est la guerre" ("then it is war"). His reply was encapsulated in Greek popular feeling in the single word "No" (Ohi). "Ohi Day" is still celebrated in Greece each year. A few hours later, Italy invaded Greece from Albania and started the Greco-Italian War.

Thanks to preparations and an inspired defence the Greeks were able to mount a successful defense and counter offensive, forcing the Italians back into Albania and occupying large parts of Northern Epirus (Southern Albania). Metaxas never saw the German invasion of Greece during the Battle of Greece because he died in Athens on January 29, 1941. Metaxas died of a phlegmon of the pharynx which subsequently led to incurable toxaemia. He was succeeded by Alexandros Koryzis. After the death of Metaxas, the Germans invading Greece encountered much difficulty with the fortifications constructed by Metaxas in Northern Greece. These fortifications were constructed along the Bulgarian border and were known as the Metaxas Line.

To this day, Metaxas remains a highly controversial figure in Greek history. He is reviled by some for his dictatorial state, and admired by others for his popular policies, patriotism, defiance to aggression, and his military victory against Italy.