The 2 p.m. EDT event is expected to focus on jobs and the economy. Twitter "curators" will help select questions for the president that are representative of the most popular topics submitted online, the White House said.
While questioners will have to limit their inquiries to 140 characters, Twitter's maximum message length, the president will have no such restrictions. Instead of answering via Tweet, Obama will go the more traditional route and answer verbally in front of a live audience gathered in the East Room of the White House.
Video of the town hall will also be streamed live online. Twitter co-founder Jack Dorsey will serve as the moderator.
The town hall will also mark the first White House "Tweetup" - that's an in-person gathering of people who are connected through Twitter.
The White House invited about 30 people who follow the administration's official Twitter account, (at)WhiteHouse, to come to Washington to take part in Wednesday's event. The invitees will also meet with senior administration officials following the town hall to share their thoughts on the issues that are important to them, the White House said.
Obama has taken questions from the public via social media, including Twitter, before. In April, he took part in a town hall hosted by Facebook.
White House communications director Dan Pfeiffer said the president sees social media as a way to reach beyond the mainstream media and connect with voters outside of Washington.
Twitter users are being asked to submit questions using the hashtag (hash)AskObama.
Hours ahead of the town hall, questions were coming in from some of Obama's political rivals. House Speaker John Boehner, who goes by the Twitter handle (at)SpeakerBoehner, asked "Will you take tax hikes off the table, or tell the American people how raising taxes will create jobs?"
Republican presidential hopeful Mitt Romney - (at)MittRomney - stuck with the same theme, asking simply, "Where are the jobs?"
