Founded in 1841 as the newly independent country's first financial institution, it has long been the largest Greek bank, a position it still held in the early 21st century.

[9][10] NBG offers financial products and services for corporate and institutional clients along with private and business customers.

The Banque d'Orient kept its branches in Salonica and Smyrna, which were part of the Ottoman Empire at the time, and Alexandria in Egypt.

However, in 1923 the Treaty of Lausanne provided for a compulsory exchange of populations between Greece and Turkey, leading to the departure of the Greeks from Smyrna.

The influx of more than 1 million refugees to Greece during this period created several challenges; NBG played a pivotal role in their settlement with loans and related instruments.

In 1930 NBG and Bank of Athens combined their activities in Egypt into a joint subsidiary, Banque Nationale de Grèce et d'Athènes.

Then in 1939, on the eve of the Second World War, the NBG established a subsidiary in New York City, the Hellenic Bank Trust Company.

Both banks cooperated before in their foreign branches in Middle East which were operated as Banque Nationale de Grèce et d'Athènes.

The next year the Greek government dissolved the insolvent Arab Hellenic Bank at a cost to Greece's Deposit Guarantee Fund of €1.5 million in payments to depositors.

In 1998 the Swiss architect Mario Botta won the competition for the new wing of the headquarters, the building was completed in 2001.

In April 2000, in a joint deal with the European Bank for Reconstruction and Development (EBRD) and IFC, NBG acquired a majority stake in Stopanska Banka (Skopje, North Macedonia).

The next year, NBG bought Banca Romaneasca, a Romanian bank, and currently holds 88.7% of all outstanding shares.

However, while it was expanding to Southeast Europe, NBG was retreating in North America and other places serving the Greek diaspora.

At home, in 2005, as part of the NBG Group's ongoing effort to improve its portfolio structure and effectively respond to changes in the domestic and international markets, the Boards of Directors of National Bank of Greece S.A. and National Investment Company S.A. decided to merge the two companies through absorption of the latter by the Bank.

Some weeks after the proposed buyout that fell through, NBG presented the plans to reduce the staff of the new banking group, many of them by taking early retirement.

The European Commission in July 2014 approved restructuring plans for NBG after finding that state aid was not hampering competition.

While the year-to-date plunge of 91% was a major factor, the exchange stated that the National Bank of Greece is no longer suitable for listing based on "abnormally low" prices of the ADRs, pursuant to Section 802.01D of the NYSE Listed Company Manual.

National Bank of Greece has faced bad loans due to the debt crisis in the country and has opted for securitizations projects since 2020.

[37] National Bank of Greece's impaired loans fell to 4.2 billion euros in the first quarter of 2021.

[38] In July 2021, NBG picked DoValue, Bain Capital and Fortress as preferred bidders on bad loans sale.

[39] In November 2023, the HFSF reduced its stake in NBG from 40.39% to 20,39%, as part of a broader re-privatization of Greek lenders bailed-out during the crisis.

The NBG conducts philanthropy through the Cultural Foundation of the National Bank and other endeavours like book printing and theatres.

During the crisis in Greece the situation of the health sector is very difficult, the NBG built a new wing of the Evangelismos Hospital in Athens.