Enyimba defeated Etoile Sahel of Tunisia 5-3 on penalties after the teams finished 3-3 on aggregate.
Enyimba defeated Julius Berger 2-0 in Aba on Wednesday, with Chukwudi Nwogu scoring in the 30th minute.
BBC: SPORT | Football | African | African leagues round-up: 14-20 May
But Enyimba are expected to poach the best players in the domestic championship as replacements for the 2005 challenge.
Emeka Nwanna scored 10 minutes before half-time to give Enyimba the lead after the visitors had squandered a penalty.
The winner came through Onyekachi Okonkwo in the 90th minute, which sent the Enyimba bench into a jubilant mood.
BBC: SPORT | Football | African | Violence mars Enyimba victory
Merreikh have the former Enyimba star Stephen Worgu on their books but he still needs to prove himself in Sudan.
Defending champions Enyimba returned triumphant to domestic action after their Champions League set back against Petro Luanda of Angola last weekend.
BBC: SPORT | Football | African | African leagues round-up: 14-20 May
Only a handful of players, including Romanus Orjinta, Mike Ochei and the controversial Ahmed 'Yaro Yaro' Garba, quit Enyimba after last year's triumph.
But despite dominating the game, Enyimba did not open scoring until the 87th minute, when substitute Omolade Ajibade finished off a smooth move.
BBC: SPORT | Football | African | Violence mars Enyimba victory
Enyimba are joined in the final four by Tunisia's Etoile Sahel, who topped Group A despite their 3-2 defeat by Africa Sports in Abidjan.
Nigerian side Enyimba, the defending champions, are in Group A with Tunisia's Etoile Sahel, Ivorian side Africa Sport and newcomers Bakili Bullets of Malawi.
The Tunisian side made their intentions of settling for a draw clear by stringing five players across the back, inviting Enyimba to come at them.
With the recent coaching saga befalling the national team there are also hopes in Nigeria that Enyimba's success can filter through to the Super Eagles.
BBC: SPORT | Football | African | Enyimba win delights Nigeria
With the Enyimba defence waiting in vain for the offside flag, Zitouni found himself unmarked in the six-yard area but headed over the bar from close range.
Enyimba's win means Sudanese side Al Hilal drop to second in the group as they could only draw 1-1 with CotonSport of Cameroon in Omdurman on Friday .
Enyimba now play Group B winners Esperance in the semi-finals.
Obinna Nwaneri, who stepped up to tuck away the decisive fifth penalty during the shootout, was also confident Enyimba can win the competition a record three times in succession.
"We have proved to be the best team in Africa and are capable of winning the competition a third time next year, " said the big defender who captained Enyimba on Sunday.
Esperance had seemed on their way to a priceless victory when midfielder Jaouar Mnari scored with a sensational right-footed volley from the edge of the Enyimba box with only 13 minutes to go.
Simba, now third in Group A with four points, will be hoping Asec - currently at the bottom of the group - could get their first win of the competition against Nigeria's Enyimba on Sunday.
He replaces Kenyan James Sianga'a, who was sacked despite making Simba the surprise team of the 2003 Champions League, by guiding them to the group stages of the competition, including a win over eventual champions Enyimba.
Over in Nigeria, Uche Kalu's first half brace and Junior Osagie's strike in the 75th minute helped Enyimba to a 3-0 victory over DR Congo's AS Vita Club in Aba to force the game into penalties.
Meanwhile, Esperance striker Ali Zitouni, who must have felt very lonely playing as the sole striker against a four-man Enyimba defence, also had a great chance to give his side the lead in the 10th minute during a rare foray upfield.
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