With swimming due to complete its programme on Saturday, the transition to athletics begins at the 80,000-capacity Olympic Stadium with the women's 10,000m and men's shot put to be decided.
British athletics' golden girl Jessica Ennis will also make her entrance as the opening rounds of the heptathlon get under way, while Welsh 400m hurdles world champion Dai Greene also begins his preliminary rounds.
Former world champion Ennis, who most recently won silver medals in the 2011 worlds in Daegu, and world indoor pentathlon in Turkey in March, missed the Beijing Olympics through injury is under pressure to perform.
Up against Ennis will be Russian world champion Tatyana Chernova and Ukraine's Natalia Dobrynska, who won the 2012 world indoor pentathlon title just days before her husband and coach, Dmytro Polyakov died.
The women's 10,000m has been built up as a duel between Kenya's world champion Vivian Cheruiyot and Ethiopia's defending Olympic champion Tirunesh Dibaba, with both eyeing a middle-distance double.
Dibaba has been wracked by injuries since her double gold medal-winning performances in Beijing, and will be bidding to emulate her cousin Derartu Tulu by winning two Olympic gold medals in the women's 10,000m.
Cheruiyot comes to London in great form, however, and will seek to carry on her imperious form from last summer's Daegu worlds when she won the 5000-10,000m double.
The shot put sees 22-year-old world and European champion David Storl of Germany taking on a strong US trio of throwers led by Reese Hoffa.
At the Aquatics Centre, Phelps will aim to consolidate his position as the most decorated Olympic athlete of all time in the 100m butterfly.
Phelps roared back to form on Thursday with an imperious victory in the 200m individual medley, consolidating his newly acquired status as the most successful athlete in Olympic history with a record 20th medal.
Elsewhere, Chinese long-distance swimmer Sun Yang will begin his quest for a second gold after his breakthrough win in the 400m freestyle.
Sun, who became the first Chinese male swimmer to win gold with his 400m free victory, opens his campaign to land the 1,500m, an event in which he set a world record last year at the Shanghai World Championships.
British hopes will hinge on the women's 800m freestyle, where Rebecca Adlington attempts to defend her 2008 crown.
A total of 22 gold medals are to be decided on Friday, with other sports in the spotlight including track cycling at the Velodrome, which got off to an explosive start on Thursday with four world records, and judo, which sees the entrance of the heavyweights.
At Wimbledon, the men's and women's singles events see home hope Andy Murray facing Novak Djokovic with a place in the final at stake. World number one Roger Federer faces Juan Martin Del Potro.
In the women's draw, Serena Williams takes on Victoria Azarenka while Russia's Maria Sharapova plays compatriot Maria Kirilenko.