On October 1, 1862, the regiment moved to Frederick, Maryland, and a week later joined General George Meade's Division of Pennsylvania troops, above Sharpsburg, and near the battle ground of Antietam.

After reaching Warrenton, where McClellan was replaced by Major General Ambrose Burnside, it passed through Fayetteville, Stafford Court House, Brooks' Station, and White Oak Church, encamping a short time at each place.

On the morning of the 13th, moving forward over the broken ground near the Run, it crossed the Bowling Green Road, and took position opposite a wooded hill on which the enemy lay in well provided breast-works.

The line of battle of the division having been somewhat disordered by the inequalities of the ground over which it had passed, and the obstructions met, it was here partially re-formed, and the position held without further orders, under a hot fire from all directions.

During Sunday, the 14th, and Monday, the 15th, the position was retained, in the hope that the enemy might be tempted from his fastness on the wooded heights, to the open fields below; but finding no indications of a hostile movement on his part, the army was withdrawn, and the regiment retired to camping ground near White Oak Church.

The loss in the campaign was one hundred and eighty, chiefly sustained in the action at Fredericksburg, including two officers killed, Lieutenants George W. Brickley and M. W. C. Barclay, for lost to the service:one by wounds, and one from sickness.

This and another fruitless expedition to Port Conway, which the rebels, from the southern shore of the Rappahannock, were suspected of visiting, were the only variations from the usual routine of camp duty experienced during the winter.

Soon afterwards it moved to the north, and united with the left of the First Division, under General Wadsworth, arriving in time to meet an advance of the enemy through the woods to the west of the Theological Seminary.

With his numerous batteries, the enemy kept up a vigorous shelling of the position, until he made his final assault at half past two in the afternoon, advancing from the north and the west in overpowering force.

The 151st Pennsylvania having been previously detached to support the Second Brigade, commanded by General Roy Stone, was posted near the pike, farther to the right, and just in rear of the Seminary, but was subsequently brought up and formed on the right of the 142nd.

Clinging to this until a large portion of the troops engaged, and the artillery and ambulances had passed on through the town, the brigade withdrew to Cemetery Hill, and re-formed in rear of its crest.

On the following day, the brigade occupied a position on the Taneytown Road, to the left of the Cemetery, and during the cannonade in the afternoon, was much exposed, the enemy's shells, from opposite directions, frequently bursting in the same field.

Early on the morning of the 3rd, it was moved into line of battle on the left center, the regiment occupying a position immediately in front of General Doubleday's headquarters.

As the rest of the army came up, the division moved out towards the Chantilly battle ground, and upon the abandonment of offensive operations by the enemy, and his consequent retirement, advanced again towards Haymarket and Thoroughfare Gap.

At Haymarket, a force of the enemy, supposed to be Stuart's Cavalry, dismounted, attacked at night, and in the conflict the regiment received a volley in the darkness, but fortunately without loss.

By this change, the 121st became part of the Fifth Corps, and though increased in numbers by the addition of a full company, which had been on duty at headquarters, was never after able to bring more than two hundred men into the field, no facilities having been afforded for recruiting.

On the following morning, having crossed the Rapidan at Germania Ford, it moved forward, and as it became evident that the enemy was in front, took position in a dense thicket, through which it was compelled to cut alleys before it could advance.

Late in the afternoon the enemy, with a recklessness rarely witnessed, charged upon the works, and in face of the deadly volleys of the infantry, and the more terrible fire of the artillery, succeeded in carrying a part of the line on the left, and in planting two of his standards upon the defenses.

All night long the march was continued, reaching Laurel Hill, on the morning of the 8th, relieving a portion of the First Division, of the Fifth Corps, which was engaging the enemy under a heavy cross-fire from batteries in position on an eminence to its left.

The next night a second line in rear of the first was thrown up, and on the 12th the command again advanced in column, under a heavy cross-fire of artillery; but after a fierce struggle, in which many of the bravest fell, it was compelled to retire.

In the action of the 10th, Captain William W. Dorr, in command of the regiment, was among the killed, At evening it was taken to the left, where it relieved a portion of the Sixth Corps, and lay during the night in line of battle.

On that day it moved on to Guinea Station, where the regiment was deployed as skirmishers, and advanced two miles, capturing a number of prisoners, and routing a rebel battery.

On June 1, the regiment advanced on the Mechanicsville Road, near Bethesda Church, under a raking fire of artillery, suffering considerable loss, but driving the rebel skirmishers, and throwing up breast-works in the edge of the woods from.

On the night of the 21st the brigade advanced in line on the left, through a thick wood, and under the fire of the rebel skirmishers threw up a breast-work, and was here employed in constructing what was subsequently known as Fort Hell.

The enemy finally advanced in column, charging the works in front of the Fourth Division, and sweeping around its left, thinking to come in upon an unprotected rear, but suddenly encountered the brigade, prepared to receive them.

On March 25, the regiment was put in motion for the final conflict at Petersburg; the assault was successful yet repelled before it reached the ground, and immediately returned to its quarters.