Representatives of the five-time Super Bowl winners will travel to England to discuss ways of maximising commercial revenues in what the Leeds website describes as "an exciting arrangement".
The Championship club's managing director David Haigh said: "This is a strategic partnership and we're looking forward to working closely with the 49ers.
"They are a worldwide brand, and we'll be discussing all aspects of our business; marketing, ticketing, merchandising, and commercial opportunities, and hopefully tapping into and sharing knowledge with them."
Chairman Salah Nooruddin told the club website: "The 49ers are market leaders in many respects, and they are excited to be working with us as we are with them."
Paraag Marathe, chief operating officer of the 49ers, said: "The 49ers are very excited about the prospect of partnering with Leeds United, a club with an international following as well as great history and tradition.
"We look forward to sharing best practices with Leeds United and providing them with our perspective on the sports industry."
Watch Leeds take on Sheffield Wednesday this Saturday, live on Sky Sports 1. Coverage begins at midday.