Alejandro de Tomaso established his company in Modena having already been involved in motorsport as a racing driver in Argentina and Europe. Most of the company's early funding came from Amory Haskell Jr. The first road-going production model was the Vallelunga, introduced in 1963: a mid-engine sports car powered by a 104 hp four-cylinder Ford Cortina engine with a fabricated steel backbone chassis — a structural approach De Tomaso would carry through subsequent models. The aluminium coupé body was designed by Fissore before production moved to Ghia; approximately 60 Vallelunga cars were built.
The Mangusta, introduced in 1966, was the first De Tomaso produced in significant numbers. Fitted with a 4.7-litre Ford V8 and clothed in steel and aluminium Ghia bodywork, the Mangusta moved the company from European to American engines. About 400 were built before production ended in 1971.
The Pantera succeeded the Mangusta in 1971 and became the most commercially successful De Tomaso model. Powered by a 351 Cleveland Ford V8 and wearing low, wedge-shaped bodywork designed by Ghia's Tom Tjaarda, the Pantera was sold through Ford's Lincoln-Mercury dealership network in the United States under a formal partnership agreement. Between 1971 and 1973, 6,128 Panteras were produced — the largest single-model production run in the company's history.
The 1973 oil crisis and quality control concerns prompted Ford to exit the deal at the end of 1973, after which De Tomaso continued producing the Pantera at a greatly reduced rate of fewer than 100 cars per year through the 1970s and 1980s. A revised Pantera 90 Si model with Marcello Gandini styling and fuel injection entered production in 1990, with 41 examples built. The Pantera was discontinued in 1993.
From 1976 to 1993, De Tomaso owned Maserati, having taken over the struggling Italian marque from Citroën with assistance from the Italian government. Under De Tomaso ownership, Maserati introduced the Biturbo, the Kyalami, the Quattroporte III, the Karif, and several other models. De Tomaso introduced platform sharing across the range to reduce development costs — the Kyalami was built on a modified De Tomaso Longchamp chassis. De Tomaso sold Maserati to Fiat S.p.A. in 1993 due to slumping sales and low profitability.
De Tomaso also owned the Italian motorcycle manufacturer Moto Guzzi from 1973 to 1993, and the car and scooter producer Innocenti from 1976 until 1993, when both were sold to Fiat.
De Tomaso made several Formula One entries from 1961 to 1963 using its own chassis. The De Tomaso 801 appeared at the 1962 Italian Grand Prix but failed to qualify. The company's most significant Formula One involvement came in 1970 when De Tomaso built a chassis designed by Giampaolo Dallara for Frank Williams Racing Cars. The car was uncompetitive and failed to finish its first four races. In the fifth race, the Dutch Grand Prix, the De Tomaso 505/38 crashed, flipped, and caught fire, killing driver Piers Courage. The partnership was dissolved at the end of the season.
The Guarà succeeded the Pantera in 1993, designed by Carlo Gaino using a combination of Ford and BMW mechanicals in a composite body, available in both coupé and barchetta form. Production was limited and sporadic throughout the Guarà's lifespan.
In the early 2000s, a planned convertible named the Biguà was developed in partnership with American firm Qvale, but the relationship soured. Qvale took over the car and sold it under their own name; MG Rover later acquired the factory and used the mechanicals as the basis of the MG XPower SV. A planned off-road vehicle project with Russian company UAZ also failed to produce any cars. Alejandro de Tomaso died in 2003, and the company entered voluntary liquidation in June 2004.
In 2009, former Fiat executive Gian Mario Rossignolo purchased the De Tomaso trademark and founded De Tomaso Automobili SpA, planning three model lines totalling 8,000 vehicles. A new Deauville concept was shown at the 2011 Geneva Motor Show but never entered production. Rossignolo was arrested in 2012 on charges of misappropriating €7.5 million in Italian government funds and was later sentenced to five and a half years in prison for fraud and embezzlement.
In April 2015, an Italian bankruptcy court approved the sale of De Tomaso to Hong Kong-based Consolidated Ideal Team Ventures for €1,050,000. At the 2019 Goodwood Festival of Speed, the revived company unveiled the P72, a retro-styled sports car paying homage to the Carroll Shelby-styled P70 of the 1960s. Built to LMP1 chassis standards on a platform shared with the Apollo Intensa Emozione and limited to 72 examples, the P72 marked the first new De Tomaso product in over a decade. In November 2022, De Tomaso announced the P900, a track-only hypercar with a 900 hp naturally aspirated V12 limited to 18 units, though the project was subsequently cancelled after production did not proceed on schedule.