Businesses must be listened to by the Government in the Brexit process as they put "evidence before ideology", Greg Clark said.
The Business Secretary issued a pointed message to Cabinet colleagues who have hit out at firms including Airbus and BMW for voicing concerns about Brexit.
Mr Clark said firms had "actual experience" of trading with the European Union rather than a "theoretical view of what the world might be like".
He insisted the Government was working to secure a Brexit deal that does not involve "customs frictions", maintains a role for the UK in standard-setting bodies and continues to allow foreign talent to come to Britain.
His comments, at the Times CEO summit, come after Foreign Secretary Boris Johnson reportedly said "f*** business" when asked about the Brexit fears of some company bosses.
Meanwhile on Sunday Jeremy Hunt and Liam Fox both rounded on aerospace giant Airbus and other firms after they questioned the Government's handling of Brexit negotiations.
But Mr Clark said: "The future of our country depends on the future of our business and that means that we must take, and act on, the advice of businesses, large and small.
"The business voice puts evidence before ideology, brings the actual experience of trading with Europe and the rest of the world not a theoretical view of what the world might be like.
"The actual experience of how supply chains work not a speculation on how they operate.
"The actual experience of employing millions of men and women of helping them earn a good living, not a theoretical exercise in which you take decisions over the lives of people in imagined worlds."
He said it was clear business leaders wanted a comprehensive agreement, "not the certain damage of no deal".
Meanwhile defence procurement minister Guto Bebb told MPs on the Commons Science and Technology Committee the comments made by Cabinet ministers attacking businesses were "unworthy and inflammatory".