Mitchell, an architect of the Northern Ireland peace agreement, is also to visit Israel and the Palestinian territories this weekend, where he'll try to kick-start peace talks with the Palestinians and discuss the recent spat between Israel and Washington over continued Israeli construction in east Jerusalem.
Diplomats at the U.S. Embassy in Damascus tell CBS News Mitchell is expected in the Syrian capital Saturday night and that he will start his official meetings Sunday morning.
It will be Mitchell's second visit to Syria since mid-June, as President Obama seeks to re-engage Damascus — a key regional player — to try and breathe new life into the faltering peace process in the Middle East.
Mitchell has made five previous visits to the region in his capacity with the Obama administration.
Former President George W. Bush put relations with Syria on hold in 2005, following the assassination of former Lebanese Prime Minister Rafiq Hariri. The Obama administration decided to return an ambassador to Damascus as a reward for Syria's help in the region and perceived attitude change, including the exchange of diplomatic representation with neighboring Lebanon and a move to boost security along its border with Iraq.
Syria remains a vital player in the Middle East. Damascus wields significant influence over events in Lebanon, is a close ally of Iran, shares a crucial border with Iraq and has a direct relationship with Palestinian extremist groups.
Mitchell's pending visit, which comes only a few days after a Middle East tour by Fred Hoff, his adviser on Syria and Lebanon, represents the administration's strongest push yet to bring regional foes to the negotiating table.
Hoff, who authored a proposal earlier this year to solve the dispute over the Israeli-occupied Golan Heights which would see the Jewish state turn much of the strategic plateau into a nature reserve accessible to both Israelis and Syrians, said after his talks with Mouallem that Washington was seeking a "balanced" role in Mideast peacemaking.
Turkey brokered four rounds of indirect talks between the two foes last year, the first such contacts since previous peace negotiations over the fate of the Golan Height were broken off in 2000.
Syria quit the talks when Israel launched a devastating offensive against the Gaza Strip, controlled since June 2007 by the Islamic militant movement Hamas. Exiled Hamas leader Khaled Mashaal lives in Damascus.
On Wednesday, in a renewed attempt by Turkey to restart negotiations between Syria and Israel, Turkish Prime Minister Recep Tayyip Erdogan met with Assad in Damascus, telling reporters Ankara had received requests to help revive the peace talks.