Lee was on the move, hoping to meet up with Gen. Joseph Johnston and his troops in North Carolina. His men arrived at Amelia Court House on April 4; looking for food and weapons, they found only weapons. In desperation, the Confederate troops took the countryside in search of food, begging the local populace to help them. In pursuit and eventually overtaking Lee's army was Union Maj. Gen. Philip Sheridan and his cavalry.

The two armies clashed on April 6, at Sayler's Creek. The result was a resounding victory for the Union; losses for Lee totaled one-quarter of his army, and among those were a handful of generals. The remaining Confederates marched on, headed for Appomattox Station and what they hoped were supply trains.

Arriving in the town ahead of Lee's army was another Union cavalry commander, Maj. Gen. George Armstrong Custer, who ordered his men to burn the supply trains that Lee's army so desperately needed. The Confederate army arrayed itself at the small settlement of Appomattox Court House. The Union cavalry under Sheridan, who had just arrived, blocked one approach out of town, and Grant had sent three corps of infantry on a hurried march to join Custer's cavalry.

At first light on April 9, Confederate troops under Maj. Gen. John Gordon attacked the Union cavalry and, pushing back the first line, found themselves face-to-face with Union infantry. Realizing that his army was far outnumbered and effectively trapped, Lee rode out with a handful of aides to request a meeting with Grant.

The two commanders traded messages for a few hours and then met at the home of Wilmer McLean. Lee, arrayed in his finest dress uniform, arrived first. Grant, who had been suffering from a severe headache, arrived in a field uniform stained with mud. The two men traded stories about the Mexican-American War, in which they had both fought, and then discussed terms of surrender.

Two days later, on April 11, the more than 27,000 remaining in the Army of Northern Virginia officially surrendered to Union troops under the watchful eye of Maj. Gen. Joshua Lawrence Chamberlain, who had led the Union defense of Little Round Top during the Battle of Gettysburg in 1863. As agreed, the Confederate troops left for their homes.

Once Lee's surrender became known to the remaining Confederate commanders, they followed suit. Johnston surrendered to Maj. Gen. William T. Sherman on April 26. The final skirmish of the war, near Brownsville, Texas, took place on May 12–13. (It was a rare Confederate victory, followed by a Confederate surrender.) The last surrender came in June.

Estimates of those killed during the Civil War vary. A conservative estimate is that the Union lost more than 100,000 killed in action and that the Confederacy lost slightly less. The number of total dead is far greater. Many suffered battle wounds that resulted in death later in life. Others had wounds that would have healed in other circumstances but were not given an adequate chance to heal.

Medical facilities during the war were filled with hazards. Medical staff did not understand the need for hygiene or the way in which some diseases spread. Doctors and nurses used the same tools over and over again, without washing the tools or their hands. Overcrowded hospitals, their ventilation poor, became breeding grounds for airborne pathogens. With people occupying the cramped conditions of army camps and army hospitals, malaria, measles, tuberculosis, and typhoid also found easy prey. Pneumonia was another potent killer, preying in those weakened from wounds or from months on end of hard fighting. Conditions in some prisons, notably the Confederate prison at Andersonville, were very harsh indeed.

A potent killer within hospitals and even within camps of able-bodied soldiers was dysentery, spread through the drinking of contaminated water. Historians estimate that dysentery killed nearly 100,000 soldiers in both armies.

The number of injured as result of the war was far higher than the death toll. Estimates were that war-related injuries topped 400,000 across both armies.

One very consequential casualty of war was the President himself. An assassin's bullet killed Abraham Lincoln before he had a chance to comprehend the scope of the North's victory. Vice-president Andrew Johnson succeeded him and went ahead with the implementation of Lincoln's plan for Reconstruction. The specifics of those programs was very different with another captain at the helm.

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