The Scottish airline will also fly to Southend from Glasgow and Aberdeen from May, with plans for Edinburgh flights later this year.
The Stornoway service, which involves a stop off at Glasgow Airport, will be also be the first ever between a Scottish island and London.
The Stornoway flights - daily execept Saturdays - will take three hours.
Southend is 53 minutes by rail from London.
Loganair managing director Jonathan Hinkles said: “We’re incredibly excited to be offering the first new routes between London and Scotland in many years, linking three Scottish airports to London Southend.”
He described it as “a hugely significant development for both Scotland-London air links and Loganair itself.
“We’re already looking at adding Edinburgh to this portfolio of London routes later in the year.
“It’s also a great honour to launch the first ever island air service direct to London, a huge boost to Stornoway’s overall connectivity.”
Inglis Lyon, managing director of Highlands and Islands Airports Limited, which runs Stornoway, said: “Loganair are to be commended on establishing this valuable new service that further improves connectivity between the Western Isles and the South of England.
“It illustrates the value of having modern, sustainable airports serving local communities.
“Islanders will benefit from excellent transport links from Southend into central London, and Loganair’s new service will also benefit inbound tourism making journeys to the islands all the more attractive to visitors keen to discover the best of what Scotland has to offer.”
Glyn Jones, chief executive of Stobart Aviation, which owns and operates Southend Airport, said: “With our own railway station just 60 steps from the terminal door, up to six trains an hour into London and our award-winning customer service, we expect these new routes to prove very popular with customers flying to and from Scotland.”