The Italian flag carrier is the first new airline to operate from the London airport since the start of the pandemic.
LCA said the route cements tourist and business links between two of Europe’s "primary financial hubs" and is used by a number of business travellers.
The new route comes as the airport reinstates all 15 of its pre-pandemic routes, with Barcelona returning to the network for the first time in almost a decade as new routes, such as Thessaloniki, join services to Split, Mykonos and Faro for summer 2022.
Latest figures indicate LCA is set to have its busiest month since the pandemic began, after it saw another post-Covid record of 44,000 passengers last week and passenger traffic up 40% on February’s figures in March.
LCA head of aviation Anne Doyere said the return of the Milan route is a "significant moment" in the airport’s recovery.
"At its peak, this route served 360,000 passengers per year and was one of our top-five performers," she added.
"We are also delighted to welcome ITA to the airport. We believe this can be the start of a very successful relationship and hopefully, over time, we can work together to add more rotations on Linate and more routes from Italy to London’s most central airport."