Mantle was born as Merlyn Louise Johnson in Cardin, Oklahoma. She was one of two daughters born to parents, Giles and Reba Johnson.

Johnson met her future husband, Mickey Mantle, while both were high school students in Oklahoma. Mickey Mantle was a baseball player at Commerce High School, while Merlyn was a cheerleader at Picher High School, a rival of Commerce. They met two years before Mantle's debut in Major League Baseball. Their first date took place at a movie theater along the famed Route 66 in Miami, Oklahoma.

Mickey Mantle and Merlyn Johnson married on December 23, 1951, following Mickey Mantle's rookie season with the New York Yankees. The couple had four sons - Mickey Jr., Billy, David and Danny. They remained married for 42 years, until Mickey Mantle's death in 1995, although they were estranged during Mickey Mantle's final years.

Mantle's husband, Hall of Famer Mickey Mantle, died of liver cancer on August 13, 1995. Her son, Billy, was diagnosed with Hodgkin's disease, but died of a heart attack in 1994, aged 36. Another son, Mickey Jr., died of non-Hodgkin's lymphoma in 2000, aged 47.

Merlyn Mantle was treated for alcoholism at the Betty Ford Clinic, a disease which also afflicted her husband and three of her sons. In an interview with the New York Daily News shortly after her husband's death in 1995. Mantle spoke of the negative impact that alcohol had over her family's life, "I was in there partying and doing the same thing as Mick. That was our life and I was part of it; I can't deny that. It ruins families."

In 1996, Merlyn co-authored a memoir of Mickey Mantle's life entitled Hero All His Life. The book was co-written with her sons, Danny Mantle and David Mantle, and writer Mickey Herskowitz.

Merlyn Mantle and Greer Johnson, Mickey Mantle's agent and former live-in aide, became involved in a legal dispute over the rights to auction off Mickey Mantle's possessions in 1997. The two sides reached a settlement, ensuring the sale of some of Mickey Mantle's belongings for approximately $500,000 dollars.

Merlyn Mantle's last public appearance was on August 5, 2008, at a dinner for the memorial service of former Yankees player Bobby Murcer. She was unable to attend Murcer's service the following morning due to health issues.

Merlyn Mantle died of pneumonia at a hospice in Plano, Texas, on August 10, 2009, at the age of 77. She had been suffering from Alzheimer's disease. She was survived by two of her four sons, David and Danny, four grandchildren, and her sister, Pat LaFalier. She will be interred next to her husband and two sons at Dallas' Sparkman-Hillcrest Memorial Park Cemetery.