Motsepe was speaking at the conclusion of his visit to Senegal, his first since the CAF Appeals Board stripped the Teranga Lions of their AFCON 2025 title and handed it to Morocco.
The ruling led the Senegalese government to accusing CAF of corruption, and Motsepe says they are ready to cooperate in any investigation.
"I welcome any investigation, whether it's by a government, an authority or anybody – I welcome and support that because any corruption in CAF, we want to know about it and we will take action ourselves immediately," said Motsepe.
"We have a duty to our people in Africa – if, as I said, any government, institution, please go ahead, conduct the investigation, we will give you all the cooperation.
"In fact, I encourage you, and if you know anything, let us know because I can tell you, whilst I'm president of CAF, we will never conceal any corruption and I'll tell you why.
"Because it is more important – let me put it this way, corruption is worse than COVID, corruption is worse than illnesses and it's worse than Cancer."
Allegations of corruption at CAF and in African football are not new, especially regarding decisions on match officiating and judicial bodies, and Motsepe says these are among the things they want to eradicate.
"It is the biggest problem, not just in football, because I've been told there have been problems in the past and corruption, and we've intervened, but we can't set a bad example in football to give our children the perception that, if you want to succeed in life, be corrupt," he added.
"You are destroying this continent, and it's not just corruption in sports, it's corruption in business – there's got to be zero tolerance of corruption in business and also in politics, and anywhere on our continent and in the world.
"That's the best gift we can give football in Africa – and not just talking about corruption but intervene, put the necessary laws and implement them, and take action."