Finally offered the chance to open his own restaurant at the age of thirty-four, he was able to create the restaurant he really wanted. In 2008, Francesco Mazzei opened L’Anima. His menu featured dishes from Calabria, Puglia, Sicily and Sardinia – simple but exceptionally tasty plates which showcased the vegetable, fruit and seafood preparations that are common in those regions. Highlights included Lobster spaghetti, Sicilian rabbit stew and light summery desserts such as Sweet Eve Strawberry soup and Mosto Cotto.

The food at L’Anima was been received with critical acclaim, with Jay Rayner describing it as showing 'a clarity and a simplicity which encourage me to reach for shamefully winsome analogies to the songs of nightingales and glacial mountain air and unsullied virgins perfumed with mint and jasmine… the simple done boisterously well.' The time he spent perfecting his dessert skills was clearly not in vain, with Rayner continuing: 'For finally came dessert, which is where Mazzei's youthful experience in his uncle's gelateria kicks in. This man understands sweet things like nuns understand praying… When food is as good as this, when the sensual and the physical become one, it does indeed transport you to another place.'

A long promoter of Calabrian and southern Italian specialities, Francesco returns home to seek out new products every two months. He worked together on a project with Pizza Express to create their spiciest pizza, The Calabrese, and is proud of the effect this partnership has had on the region. Pizza Express now source their salami from Calabria, which has provided jobs in what is the poorest part of Italy.

Francesco has worked with the Calabrian government, consulting on how to promote their artisan foodstuffs outside of the country. He has been an ambassador for the citrus fruit bergamot and the spicy sausage ‘nduja, both of which are produced in the region, and he is credited with single-handedly bringing the latter – a sweet, spreadable pork sausage, spiked with chilli – to the restaurants and dinner tables of Britain. Since 2007 he has made frequent appearances on the BBC, including Saturday Kitchen and Masterchef, and is a regular at the Taste of London festival. He uses these opportunities to introduce creative applications of Calabrian ingredients to a wider audience, such as his fillets of wild boar marinated in liquorice, bergamot and chilli.

In March 2015, Francesco left L’Anima – now considered one of the capital’s best Italian restaurants – to focus on other projects. He released a cookbook, Mezzogiorno: Francesco Mazzei Recipes from Southern Italy, in the autumn of that year. But he finally returned to the professional kitchen at the end of the year at Sartoria, the only restaurant on Savile Row in Mayfair. The entire interior was given a full refurbishment before Francesco arrived, and he was able to place his unmistakable southern Italian stamp on the menu. Two restaurants followed shortly after – Radici, in Islington, allowed Francesco to return to his Calabrian roots, cooking simple, rustic fare in a more relaxed setting, while Fiume, in Battersea, became another ode to southern Italian cooking.

In April 2023, it was announced that Francesco would leave D&D London, with which he had opened the restaurants, to spend more time travelling and focusing on his charity work. While Radici closed in January 2023, both Sartoria and Fiume remain open. Francesco moved onto a residency at Villa Corinthia in Malta, but in autumn 2024 announced he would be partnering with Corinthia London to open a new Italian restaurant there, taking over from The Northall.