Williams is the top seed and No. 1 player in world rankings, and thus the heavy favorite to reach Sunday's final at Flushing Meadows.
However, Makarova is on her best run at a major tennis tournament. Plus, she can take heart from having defeated Williams in straight sets at the 2012 Australian Open.
Makarova has no fear as she bids to realize a childhood dream.
"It's special, but I'm not thinking all the time I'm in a grand slam against Serena," she said.
"To win the grand slam [is] always the dream. From the kid when I was going to school and then came back home and watching some matches.
"You don't believe that you can be here, and finally you're here and going so far."
Makarova is the tournament's 17th seed, and a victory over Williams would be the latest in the upheaval at this year's Open.
The winner will meet either Shuai Peng or Caroline Wozniacki, who met in Friday's first semifinal.