Born in 1790 in Argostoli he belonged to the historical Metaxas family, which originated in Constantinople and moved to Kefalonia in the 15th century. He was the second son of Petrod Metaxas and Violeta Loverdou and had three brothers, Anastasios, Paisios and Ioannis. Konstantinos Metaxas was his cousin. Although he didn't receive any special education, other than Greek he was fluent in Italian and French and was a scholar of ancient Greek history. A few years before the Greek Revolution he married Marietta Vourvachi, sister of a Greek officer in the French army, Dionysios, with whom he had two sons (Spyros and Petros) and two daughters. In pre-revolutionary years, he worked as a solicitor.
He was initiated into Filiki Eteria. When the revolution was declared, he rushed to Peloponnese and established, along with his brother Anastasios and his cousin Konstantinos, a military contingent of 350 men from Kefalonia equipped with two cannons, contribution of Evangelinos Panas. Among the leaders were Victor Gerasimos Fokas, Konstantinos Fokas Karandinos and others. Claiming that they were chasing pirates, they boarded a ship belonged to Anastasios and Fokas Theodoratou brothers, which was equipped with 18 cannons, 50 sailors and 50 gunmen. They disembarked in early May 1821 in Glarentza and marched to Manolada. There, they were joined by other military captains (Vilaetis, Sisinis and Plapoutas) and then marched to Lalas, which was the foothold of notorious Albanian fighters. During the battles that took place in the region and until June 13, when all the people from Lalas had to resort to Patra, Metaxas was among the noteworthy. He even got wounded in both hands by bullets. Later, after Demetrios Ypsilantis' suggestion, he was sent, along with the rest of the army, to Patra. Soon, due to his injury, he was only active in the political part of the revolution.
On May 25, 1822 in a unanimous decision, the "Executive Body" passed an act by which Metaxas, was naturalized as a Greek Peloponnese citizen for his service to his country. He was appointed Minister of Police in 1822, while in April 1826 was appointed Minister of War. He was a member of the National Assembly of Argos and member of the Provisional Government. Along with Georgios Mavromichalis and Germanos III of Old Patras, he was sent by the Government to Verona in search for financial resources but also to persuade the Great Powers to not act against Greece, in which he succeeded with the help of his friend Ioannis Kapodistrias.
Andreas Metaxas was the prime mover behind Ioannis Kapodistrias election. He was a devout supporter of Kapodistrias and remained his faithful ally to the end. In return Kapodistrias honored him by promoting him to high dignities. On his own initiative, he joined the "Panhellenic”, was appointed Head of the army and Emergency Commissioner of Peloponnese. From this position Metaxas mainly helped organizing the tactical army. After the assassination of Kapodistrias in 1831, although pro-Russian, Metaxas opposed the election of Augustine Kapodistrias which he found disastrous. Nevertheless, he kept away from Ioannis Kolettis' disruptive tendencies. Despite that, he remained a member of the provisional government until the arrival of king Otto.
During the regency, he was appointed Prefect of Laconia and later, in October 1835, member of the State Council. Soon, however, he was exiled to Marseille by the Regency for his liberal views. He was later called back and sent to Spain as ambassador of Greece. After his return to Greece in 1839, he was re-appointed member of the State Council. He served as Minister of Military in the government of Alexandros Mavrokordatos during July and August 1841. After his resignation, he got involved in the Revolution of September 3, 1843, demanding the granting of a constitution. He took over the leadership of the Russian Party after Theodoros Kolokotronis' death.
On September 3, 1843, as a consequence of the movement that erupted on the same day, he received a mandate by Otto to form a government to vote on the Constitution. A few days later, under the threat that he would resign unless his proposal was accepted, he managed to convince the cabinet to broaden the government with the participation of Alexandros Mavrokordatos and Ioannis Kolettis, leaders of the English and French party respectively. Metaxas was the first government leader in the political history of Greece who was named prime minister.
During his premiership, Metaxas managed to maintain order and conduct elections in order to form the First National Assembly. He was elected Honorary Vice-President in five regions and participated in its actions. In next year's elections for the First Period (1844–1845), he was elected Attica MP. He was appointed Minister of Finance in Kolettis' government, a position he held from August 1844 until August 1845, when he resigned after Kolettis' effort to overthrow the constitution. He served as a senator during the years 1846 and 1847 and from 1850 until 1859 as an Attica MP. In 1850, he was promoted to the rank of Lieutenant and was decorated by King Otto with the Grand Cross of the Order of the Redeemer. On the 15th of September of the same year, he was sent to Istanbul as ambassador of Greece.
He resigned on March 10, 1854, after the start of the Crimean War, and returned to Athens where he retired from politics. It appears that he secretly supported the revolt movement of Thessaly and Epirus and changed the King's hasty decision to get involved, when he secretly rushed to the palace and convinced him not to go there, thus preventing any suffering for Greece. Shortly before his death, Otto assigned him to form a government but he refused.
Andreas Metaxas also served as president of the Society for the Promotion of Education and Learning and many charity foundations. Throughout his life he was brave, honest, patriotic and had a strong character. He died in Athens in September 1860.