In March 1864, Grant was summoned from the Western Theater, promoted to lieutenant general, and given command of all Union armies. Maj. Gen. William Tecumseh Sherman succeeded Grant in command of most of the western armies. Grant and President Abraham Lincoln devised a coordinated strategy that would strike at the heart of the Confederacy from multiple directions: Grant, Meade, and Benjamin Butler against Lee near Richmond, Virginia; Franz Sigel in the Shenandoah Valley; Sherman to invade Georgia, defeat Joseph E. Johnston, and capture Atlanta; George Crook and William W. Averell to operate against railroad supply lines in West Virginia; and Nathaniel Banks to capture Mobile, Alabama. This was the first time the Union armies would have a coordinated offensive strategy across a number of theaters.

Although previous Union campaigns in Virginia targeted the Confederate capital of Richmond as their primary objective, this time the goal was to capture Richmond by aiming for the destruction of Lee's army. Lincoln had long advocated this strategy for his generals, recognizing that the city would certainly fall after the loss of its principal defensive army. Grant ordered Meade, "Wherever Lee goes, there you will go also." Although he hoped for a quick, decisive battle, Grant was prepared to fight a war of attrition. He meant to "hammer continuously against the armed force of the enemy and his resources until by mere attrition, if in no other way, there should be nothing left to him but an equal submission with the loyal section of our common country to the constitution and laws of the land." Both Union and Confederate casualties could be high, but the Union had greater resources to replace lost soldiers and equipment.

Crossing the Rapidan River on May 4, 1864, Grant sought to defeat Lee's army by quickly placing his forces between Lee and Richmond and inviting an open battle. Lee surprised Grant by attacking the larger Union army in the Battle of the Wilderness (May 5–7), resulting in many casualties on both sides. Unlike his predecessors in the Eastern Theater, Grant did not withdraw his army following this setback but instead maneuvered to the southeast, resuming his attempt to interpose his forces between Lee and Richmond but Lee's army was able to get into position to block this maneuver. At the Battle of Spotsylvania Court House (May 8–21), Grant repeatedly attacked segments of the Confederate defensive line, hoping for a breakthrough but the only results were again many losses for both sides.

Grant maneuvered again, meeting Lee at the North Anna River (Battle of North Anna, May 23–26). Here, Lee held clever defensive positions that provided an opportunity to defeat portions of Grant's army but illness prevented Lee from attacking in time to trap Grant. The final major battle of the campaign was waged at Cold Harbor (May 31 – June 12), in which Grant gambled that Lee's army was exhausted and ordered a massive assault against strong defensive positions, resulting in disproportionately heavy Union casualties. Resorting to maneuver a final time, Grant surprised Lee by stealthily crossing the James River, threatening to capture the city of Petersburg, the loss of which would doom the Confederate capital. The resulting siege of Petersburg (June 1864 – March 1865) led to the eventual surrender of Lee's army in April 1865 and the end of the Civil War.

The campaign included two long-range raids by Union cavalry under Maj. Gen. Philip Sheridan. In a raid toward Richmond, Confederate cavalry commander Maj. Gen. J.E.B. Stuart was mortally wounded at the Battle of Yellow Tavern (May 11). In a raid attempting to destroy the Virginia Central Railroad to the west, Sheridan was thwarted by Maj. Gen. Wade Hampton at the Battle of Trevilian Station (June 11–12), the largest cavalry battle of the war. Although Grant suffered severe losses during the campaign, it was a strategic Union victory. It inflicted proportionately higher losses on Lee's army and maneuvered it into a siege at Richmond and Petersburg, Virginia, in just over eight weeks.