The Prime Minister said the whole country will “reap the rewards” of a predicted multibillion pound boost to the economy, as the new railway line transports passengers from Tuesday.
The delayed and overbudget line will boost capacity and cut journey times for east-west travel across the capital.
Services will begin in new tunnels under the centre of the city at 6.30am.
Large numbers of transport enthusiasts are expected to be on the first departures.
Mr Johnson said: “As the Elizabeth line opens to the public, we know it’s not just Londoners that will reap the rewards, but the whole country – because better transport grows the economy, levels up opportunity and creates jobs.”
The Government said the Elizabeth line project is supporting 55,000 jobs, 1,000 apprenticeships and is forecast to boost the economy by £42 billion.
The mayor of London, Sadiq Khan, echoed the PM’s sentiments, saying the line’s opening would “provide a crucial economic boost to the whole country”.
Mr Khan, who was due to be on the first train from Paddington on Tuesday, said: “Today is a historic day as the Elizabeth line opens to passengers. This is a huge moment, not just for London but the entire country, particularly in this special Jubilee year.
“This brand new line is the most significant addition to our transport network in decades.
“It will add billions to our economy and is set to serve up to 200 million passengers each year. I’m sure passengers will enjoy the modern trains, beautiful step-free stations and the reduced journey times across the capital and the South East.
“The Elizabeth line is much more than just a new railway, it will provide a crucial economic boost to the whole country and help to turbo-charge our recovery from the pandemic.”
The line stretches from Reading in Berkshire and Heathrow Airport in west London to Abbey Wood in south-east London and Shenfield in Essex.
It will beginning operating in three separate sections, which are expected to be integrated in the autumn.
Transport for London (TfL) estimates that annual passenger numbers will reach 170 million by 2026.
The new central section, built by the Crossrail project, runs through tunnels from Paddington in west London to Abbey Wood.
It will initially be closed on Sundays, apart from during the Platinum Jubilee weekend, to allow further testing and software updates to take place.
Crossrail suffered numerous issues including construction difficulties and complications installing signalling systems.
It was due to be completed in December 2018 and was set a budget of £14.8 billion in 2010.
The final total cost has been estimated at £18.9 billion, including £5.1 billion from the Government.
The line is named in honour of the Queen, who visited Paddington station last week to celebrate the completion of Crossrail.