Sergio Mantegazza was born in Lugano, Switzerland, to Antonio and Angelina Mantegazza in 1927. He has a brother, Geo Mantegazza. He was educated at Istituto Elvetico. and Gademann Business School.

As a young man, Mantegazza developed further Business and entrepreneurial skills by working in the family Business after leaving education. Founded by his Father Antonio in 1928, Globus Viaggi initially started with a single gondola ferrying tourists and goods across and around Lake Lugano, Switzerland. Antonio Mantegazza went on to acquire a fleet of 12 coaches to transport tourists around the area. By 1950, the company operated 33 coaches with the addition of overnight excursions to Rome, Venice and the French Riviera.

His other son, Fabio Mantegazza (born 1955), was working with Sergio in the United Kingdom, and was CEO and chairman of Monarch Travel Group Ltd.

His daughter, Maria Dolores Mantegazza (born 1956), serves as a trustee to the Sergio Mantegazza Charitable Foundation in Canton Ticino alongside Fabio Mantegazza and Geo Mantegazza. The Foundation focuses on supporting various charities within the arts and youth Sports programs as well as education and medical-related areas. Mantegazza also remains active in the organisation.

In 1961, the Globus group launched Cosmos Holidays in the United Kingdom and air holiday packages to southern Europe. This led to other destinations like Canada, Australia and New Zealand.

Mantegazza took over as President of Globus in 1975 and expanded the travel and tour Business, introducing travel packages to Africa, Australia and South America. Globus also launched its North American company Group Voyagers, overseeing US tour operations and the American market for the Globus and Cosmos brands. In 2003, Avalon Waterways and Monograms were also created, focusing on independent travel and river cruises.

His son, Paolo, worked for Bankers Trust and Credit Suisse, before becoming President and CEO of Globus' US Business Group Voyagers in 1998, and killed himself in 2004, at the age of 34.

Mantegazza joined the British Travel Industry Hall of Fame in 2006 alongside Sir Richard Branson, Sir Rocco Forte and Stephen Kaufer.

In October 2014, it was reported that he had sold Monarch Airlines to Greybull Capital. This deal involved the company's pension scheme transferring into the statutory Pension Protection Fund (PPF), causing 70 Monarch pilot's pension benefits to be affected by the PPF compensation cap. The Pension Regulator's subsequent statutory report later concluded that the majority of scheme members received 90% or more of their benefits. However, the deal was nonetheless criticised by The Guardian, which stated that the pilots' retirement plans had been "wrecked", and as stated by Frank Field MP, Chairman of the Work and Pensions Select Committee, in a letter to the Pension Protection Fund - "Compared to the hundreds of millions pounds of debt they were being released from, the [pension] deal was a good one for the Mantegazzas only." Alan Rubenstein, chief executive of the Pension Protection Fund, gave a response to Mr Field, saying the deal reached over the pension scheme was better than no deal at all. "Given that the recover to the Monarch scheme in the event of insolvency would have been zero, we and ultimately our levy payers are £30m better off as a result of the upfront cash payments we negotiated."