Zagunis is after a third straight gold medal, winning both events since women's saber was included in the Olympic fencing schedule in Athens in 2004. That victory made her the first American to collect gold in Olympic fencing.
She also took bronze with the American team in Beijing four years ago.
"For me, I'm really treating this like it's my first time at the Olympics," said Zagunis, adding she won't be thinking of any of her past Olympic victories.
"I'm just going into this tournament thinking this is it, this is all that I've got and I'm going to put it all out there," said Zagunis, who will open her quest for a third gold against Diah Permatasari of Indonesia.
Following up on her Beijing triumph, Zagunis won back-to-back world titles in 2009 and 2010 but was defeated in last year's final.
World champion Sophya Velikaya of Russia will again be among Zagunis' main challengers, while third-ranked Olga Kharlan will be bidding for a second fencing gold medal for Ukraine after Yana Shemyakina won the individual epee Monday.
Also Wednesday, top-ranked Nikolai Novosjolov of Estonia and world champion Paolo Pizzo of Italy are gold favourites in the men's individual epee.
Defending champion Matteo Tagliariol failed to qualify after a disappointing season, which saw him stumbling out in the opening round of last year's world championships in Catania, Sicily.
Second-seeded Fabian Kauter of Switzerland and Bas Verwijlen of the Netherlands could spoil the party for Novosjolov and Pizzo.
Kauter is a European and world championship bronze medallist , while Verwijlen made it to the final of the 2011 worlds and has climbed to sixth in the epee rankings.
These are the final two individual fencing competitions at the Olympics. The team events are coming up, with the women competing in foil and epee and the men in saber and foil.