The widening of the A23 between Handcross and Warninglid in West Sussex is the first of the 14 major road projects Government pledged to start before 2015.
It sets the ball rolling on a £1.4bn Government package of strategic road projects to boost the economy.
The first phase of work will be site preparation before main civil engineering work begins next spring.
Roads Minister Mike Penning said: “This start of work shows the Government delivering on its promise to invest in transport schemes that reduce congestion, improve safety, and support economic growth.
“The A23 is a vital economic link between the capital and the south coast, and is used by more than 70,000 vehicles every day.
He added: "This major improvement project will provide much-needed extra capacity at a notorious traffic bottleneck, deliver important safety benefits for drivers and provide more than a six-fold return on investment for the economy.”
The A23 bottleneck will be widened to three lanes in each direction.
The road layout will be upgraded, improving visibility for road users and removing sharp bends, and access to the A23 will be made safer for the homes and businesses where drivers currently have to turn directly onto the busy dual carriageway.
Before main civil engineering work can start, trees and other vegetation in the central reservation and verges along the A23 need to be removed.
Highways Agency project manager Chris Bacon said: “By using the space in the central reservation we are minimising the amount of land we will need on either side of the road, and we will also carry out further replanting later in the project."
The work will be carried out using a series of overnight restrictions on the A23 between Pease Pottage and Bolney over the next seven weeks.
Overnight lane restrictions will begin this Sunday (9 October) and will be followed by a series of overnight carriageway closures in November, for which fully signed diversion routes will be in place.
Main civil engineering works on the improvement scheme begin next spring. The improved road is scheduled to open in 2014.
