"As our family has faced many trials and triumphs throughout the years, you have blessed us with your prayers. We are asking for those prayers once again," Kelly said in a statement Thursday. "The oral cancer we hoped would be gone forever has returned. Although I was shocked and deeply saddened to receive this news, I know that God is with me.
"I continuously talk about the four F's: Faith, Family, Friends and Fans. With all of you by my side, we will fight and win this battle together. Staying 'Kelly Tough' and trusting God, will carry us through this difficult time."
Kelly first announced in June 2013 that he had squamous cell carcinoma of the upper jawbone. He had surgery to remove tumors but was found again to have cancer in March 2014.
The former Buffalo Bills quarterback underwent weeks of chemotherapy and radiation in 2014 before being declared cancer-free that September. He has been periodically screened for cancer in the years since.
Kelly's daughter, Erin Kelly-Bean, and his wife, Jill, posted messages to Instagram on Thursday.
Kelly, 58, played for the Bills from 1986 through 1996 and appeared in four consecutive Super Bowls. He was inducted into the Hall of Fame in 2002.
"We are deeply saddened to hear the news about Jim Kelly and his impending battle with cancer," the Bills said in a statement Thursday. "Jim is a tough and courageous man and we know he will fight this battle with strength and determination. The Buffalo Bills will support the Kelly family during this trying time and we ask our fans to pray for the family as Jim begins the treatment process and the road to recovery."