Known as "Natty", he was the son of Lionel de Rothschild (1808-1879) and Charlotte Rothschild (née von Rothschild), grandson of Nathan Mayer Rothschild after whom he was named, and the great-grandson of Mayer Amschel Rothschild founder of the dynasty.
In 1847, his uncle Anthony Nathan de Rothschild (1810-1876) was created 1st Baronet de Rothschild, of Tring Park. Because Anthony had no male heirs, on his death the title went to nephew Nathan Mayer Rothschild who was subsequently elevated to the House of Lords and created Baron Rothschild in 1885 with which title the baronetcy remains merged.
The peerage was inherited by his son Walter (Lionel Walter Rothschild, 2nd Baron Rothschild).
He worked as a partner in the London branch of the family bank NM Rothschild and Sons and became head of the bank after his father's death in 1879. During his tenure he also maintained its pre-eminent position in private venture finance and in issuing loans to the governments of the USA, Russia and Austria. Following the Rothschild's funding of the Suez Canal a close relationship was maintained with Benjamin Disraeli and affairs in Egypt.
Natty also funded Cecil Rhodes in the development of the British South Africa Company and the De Beers diamond conglomerate. He administered Rhodes's estate after his death in 1902 and helped to set up the Rhodes Scholarship scheme at Oxford University.