Dhoni, who broke the ODI jinx in Australia by winning the Commonwealth Bank series in 2007/08, has an in-form team to do the same in South Africa.
Six back-to-back ODI trophies in 11 months across four continents should easily qualify as Indian cricket's finest hour since those run-of-the-mill tours of England and Australia in 2011-12. But winning an ODI series in South Africa will be a first that India has tried in vain for 21 years.
Not just India, South Africa dominated almost every visitor since their re-entry into international cricket - until Pakistan arrived this year. The Pakistanis created history and exposed some chinks in the Proteas' armour with a 2-1 series win. That has added strength to India's conviction that the South African fortress is not unconquerable.
For the first time, India will travel to South Africa as world champions and under a leader who is the only one to have won all three ICC trophies - World Twenty20 (2007), World Cup (2011) and Champions Trophy (2013). Add the Test mace to that and it becomes an enviable captaincy record.
It was Dhoni who broke the ODI jinx in Australia by winning the Commonwealth Bank tri-series in 2007/08, and the current team and its form offers Dhoni the chance to do the same on what is possibly his last tour of South Africa.
A team that has never scored 300 in an ODI in South Africa (279 highest) is now chasing totals in excess of 350. Some will be quick to point that it happened in India and can't be compared to what the team will face in South Africa, But how many times have 350-plus scores been chased in ODI history? India did it twice in a week against Australia. No mean feat - anywhere, in any conditions, against any bowling. Have to agree.
The rise of India's new run-machines deserves most of the credit in India's dream run in ODIs. Shikhar Dhawan, Rohit Sharma and Virat Kohli have all scored more than 1000 runs this year. And hear this: Dhawan has hit five tons this year. Kohli hit India's fastest ton in 50 balls and became the joint quickest to 5000 ODI runs. Rohit re-invented himself with a double hundred - only the third man to do it.
Dhoni may not agree with the change in the ODI rules, but his batsmen, including himself as ODI cricket's best finisher currently, have almost mastered the art of taking advantage of just four boundary-riders. A ball that's never more than 25-overs old is being smacked by Indian bats. But it will be the first time Indian batsmen will try to take advantage of those rules outside the subcontinent. That's the test.
The closest India came to winning a bilateral ODI series in South Africa was in 2010/11 under Dhoni, but lost that five-match series 2-3 in the end. And to nip that threat in the bud, India's bowlers will have to be more careful than the batsmen.
Just like most other nations, Indian bowlers too are suffering the brunt of changed rules. After all, if India had to chase 350-plus totals, it's their bowlers who first conceded those. Pitches will surely be more supportive in South Africa but still there will be only four fielders outside the circle and two new balls from either end. So that remains a challenge.
For South Africa, the challenge will be to come out of the loss to Pakistan and stop the Indian juggernaut. And while they may not have to worry about the conditions, it surely will be tougher than in the past 21 years.
India's ODI record against South Africa
Overall: Played 67, won 25, lost 40, no result 2
In India: Played 23, won 13, lost 10
In South Africa: Played 25, won 5, lost 19, no result 1
Bilateral series in South Africa: Played 16, won 4, lost 12
Bilateral series in India: Played 16, won 10, lost 6