Hassan Shehata has stepped down from his role as Egypt coach.
The Egyptian Football Association accepted the 61-year-old's resignation on Monday.
Despite recent woes, Shehata leaves the Pharaohs as the most successful coach in their history, having won the last three Africa Cup of Nations.
But Sunday's failure to beat South Africa in a Nations Cup qualifier meant it was unlikely Egypt would defend their crown at the 2012 finals.
The 0-0 draw in Cairo kept the African champions bottom of Group G, without a win from four games and trailing leaders South Africa by six points with just two matches left.
The Pharaohs had needed to win last night's Cairo clash to have any realistic chance of defending their continental crown in Equatorial Guinea and Gabon.
But the goalless draw effectively dashed Egypt's hopes of making next January's finals, prompting cries of 'Shehata out' from some fans at the final whistle.
In a statement, Samir Zaher, the head of the Egyptian FA, said that "the federation has full respect for the management team over the past six years in terms of its accomplishments".
In addition to the Nations Cup titles, Shehata led Egypt to their highest Fifa ranking ever - with the Pharaohs occupying ninth spot between July and September last year, before falling to 36th position.
Having taken charge of the team in 2004, Shehata was not just Egypt's longest-serving coach but also its most successful.
He led the Pharaohs to a record three successive Nations Cups: winning on home soil in 2006 before triumphs in Ghana in 2008 and in Angola two years later.
The one major failure of his seven years in charge was the inability to qualify for a World Cup finals.
In November 2009, his team was just 90 minutes away but the likes of Mohamed Aboutreika, Ahmed Hassan and Essam Al Hadary lost a bitterly-contested play-off to North African rivals Algeria in neutral Sudan.
Shehata restored his reputation when winning the 2010 Nations Cup just two months later, but qualifying attempts for 2012 have further knocked his standing.
Their qualifying campaign got off to a stuttering start when drawing at home to Sierra Leone before the Pharaohs were surprisingly beaten 1-0 in Niger.
Another 1-0 defeat followed in South Africa in March, before Sunday's disappointing draw against the same opposition.
Shehata had been criticised in recent times for failing to replace an ageing squad as well as for non-footballing reasons.
The former forward, who contested the Nations Cup as a player, earned the wrath of many Egyptians when backing President Hosni Mubarak during the country's uprising earlier this year.
After the Pharaohs' failure to beat South Africa on Sunday, a disappointed Shehata failed to attend the post-match press conference.
The Egypt coach recently revealed that he turned down opportunities to coach the Kuwaiti and Omani national teams.
The Egyptian FA has not named a successor to Shehata, but the Pharaohs have two remaining qualifiers later this year against Sierra Leone and Niger.