Flood, the Leicester Tigers No.10, starts for the first time in this year's competition after a thigh injury ruled out Owen Farrell.
The 27-year-old sprang from the bench to guide England to victory against France and will be charged with keeping the Red Rose on the front foot at Twickenham.
Italy have already demonstrated how dangerous they can be having defeated France in the opening round and Flood accepts England cannot afford to play the Azzurri at their own game on Sunday.
"We have got to take the opportunities that come to us in terms of space and in terms of the opportunity to take them on," he said.
"We will have a real crack at them, weather depending, but it is important for us not to get stagnated and get into an arm wrestle and have a real battle.
"It is important for us to be able to manipulate the ball and move it around and that is what we'll try and do.
"The guys have gone well in the week, we've enjoyed training and it is nice to have an opportunity.
"You understand where you are and you have to keep pushing and that is what I have to do this weekend, I have to take my chance."