Dole had disclosed in February that he was being treated for stage-four lung cancer.
Former US Senator and presidential candidate Bob Dole has died aged 98, his family announced on social media.
Dole, who battled back from being severely wounded in World War II to become a five-term US senator and the Republican Party's 1996 presidential nominee, died in his sleep early on Sunday morning, according to the Elizabeth Dole Foundation.
The longtime senator had disclosed in February that he was being treated for stage-four lung cancer.
As tributes poured in for the veteran politician, President Joe Biden paid respect to his "friend" and "an American statesman like few in our history" by ordering flags to fly at half-staff on federal grounds until Thursday.
"America has lost one of its heroes, our family has lost its rock," his family said in a statement. "Our grief is softened by our gratitude for having shared in so vibrant a life."
Born July 22, 1923, Robert Joseph Dole grew up in the prairie town of Russell, Kansas, and presented himself as a plain-spoken, unpretentious man of action, rather than one of lofty ideals and soaring rhetoric.
He was elected to the US Senate in 1968 and was re-elected in 1974, 1980, 1986, and 1992, serving both as Senate majority and minority leader over the years.
In 1976, the Republican was tapped by Gerald Ford to be his vice-presidential candidate but the Republican ticket was lost to Democrats Jimmy Carter and Walter Mondale.
Twenty years later, Dole captured the Republican White House nomination on his third attempt in 1996 but went on to lose the race to Democrat Bill Clinton.
During his 35-year career on Capitol Hill, Dole became one of the most influential legislators and party leaders in the Senate, combining a talent for compromise with a caustic wit, which he often turned on himself but didn't hesitate to turn on others, too.
He played a key role in the expansion of the food stamp program in the 1970s, the extension of the Voting Rights Act in 1982, and the adoption of the Americans with Disabilities Act in 1990.
Dole was awarded the Presidential Medal of Freedom, the highest US civilian honour, by Clinton in 1997.
'A war hero, a political leader and a statesman'
"When I think of the greatest generation, I think of Senator Bob Dole – a man who dedicated his life to serving our country. Rest In Peace, my friend," tweeted Senator Mitt Romney, also a former Republican presidential candidate.
Tributes also came from Democrats. Calling Dole "a man of his word", Pelosi said the United States had lost "a towering leader who embodied courage and excellence in public service".
Former President Barack Obama praised Dole on Twitter as "a war hero, a political leader, and a statesman" whose generation placed "country over party".
Democratic Senator Bernie Sanders also sent condolences, saying: "Bob Dole served his country with courage on the battlefield, and with dignity in the Senate."
Dole has long been praised for his military service.
Enlisted as an officer in the US Army, Dole charged a German position in northern Italy in 1945 and was hit by a shell fragment that crushed two vertebrae and paralysed his arms and legs.
The young Army platoon leader spent three years recovering in a hospital and never regained use of his right hand.
To avoid embarrassing those trying to shake his right hand, Dole always clutched a pen in it and reached out with his left.
He published a memoir about his wartime experiences and recovery, "One Soldier's Story" in 2005.
In one of his rare public appearances in recent years, Dole made an emotional appearance before the casket of another World War II veteran, former President George H.W. Bush, in the US Capitol Rotunda in December 2018.
Social media tributes recalled how he insisted on standing, held up by an aide, to salute his one-time political rival with his left hand, chin quivering.
Dove devoted his later years to the cause of wounded veterans, their fallen comrades at Arlington National Cemetery, and remembrance of the fading generation of World War II vets.
He was also a driving force behind the World War II Memorial on the National Mall in Washington.
Dole is survived by his daughter Robin, and his second wife, Elizabeth Dole, who herself had a distinguished political career, serving as US secretary of transportation, secretary of labour, and senator from North Carolina.