The road, named for Israeli Prime Minister David Ben-Gurion, was originally constructed as part of the Jerusalem–Tel Aviv line, also known as Highway 1, which is based on the ancient road between Jaffa and Jerusalem via Ramla (Highway 44), Latrun, Sha'ar HaGai, and Abu Ghosh.

The section that belongs to Route 333 today is between the Sha'ar Morai interchange and the entrance to Jerusalem through Ginot Sakharov Junction.

As a result, the Ben-Gurion Boulevard was no longer officially considered part of the redrawn route of Highway 1.

Work began in March 2017 to upgrade the Ganot Sakharov Junction to an interchange, and in 2021, it was opened to traffic.

After the opening of the Ginot Sakharov interchange, Ben-Gurion Boulevard was marked for the first time as Route 333.