Mitchell said he planned to "establish a regular and sustained presence in the region".
"There are no easy or risk-free courses of action, but I am convinced ... that with patience and determined and persevering diplomacy we can help to make a difference and we can assist those in the region achieve the peace and stability that people on all sides long for."
The 75-year-old former senator was appointed by Barack Obama, the US president, in January.
On his first trip to the Middle East, Mitchell visited Egypt, Jordan, Saudi Arabia and Israel and held talks with Ehud Olmert, the Israeli prime minister, and Mahmoud Abbas, the Palestinian president.
The trip came after more than 1,300 Palestinians were killed during Israel's three-week war on Gaza. Thirteen Israelis also died.
Al Jazeera's Nick Spicer in Washington said the announcement of Mitchell's latest visit was evidence of the deepening involvement of the US government in the Middle East conflict.
Conditions on Hamas
Clinton also reiterated international demands placed on Hamas, the Palestinian movement that controls the Gaza Strip.
"They (Hamas) must renounce violence, they must recognise Israel, they must agree to abide by prior agreements," said Clinton.
"We are not able to look into the future to see whether there will be changes on the part of Hamas that [would] meet our conditions but, you know, certainly that would be a clear path for them to follow," Clinton added.
She also demanded that Hamas halts rocket fire into Israel from the Gaza Strip.
"Our conditions with respect to Hamas have not, and will not, change," she said.
Earlier on Tuesday, the Israeli army said a rocket fired from Gaza by Palestinian fighters exploded in the southern Israeli town of Ashkelon.
Israel later carried out an air raid on the Gaza Strip, hitting the town of Khan Younis.