Manhunt is the 23rd episode in the series and the first in season 2. Picking up eight hours after their escape from Fox River, Michael, Lincoln, Sucre, Abruzzi and C-Note are on the run for their lives as a vengeful Bellick leads the prison guards seeking to capture their escaped quarry; Dr. Sara is in critical condition from her overdose; Veronica finds herself a prisoner with Terrance; T-Bag tries to get the upper hand while fleeing from the authorities; and a new take-charge FBI investigator proves to be Scofield's match.
The second season opens the morning after the escape, as Michael, Lincoln, Abruzzi, C-Note and Sucre barely manage — with the help of a freight train — to elude Captain Bellick. When FBI Special Agent Alexander Mahone is assigned to lead a nationwide search for the escapees, this makes their escape even more difficult. Mahone calls a press conference, and urges everybody watching the television broadcast to find the "Fox River 8".
In the meantime, Michael, Lincoln, Abruzzi, C-Note, and Sucre are found by a hunter, and held at bay when the hunter brandishes his rifle. Abruzzi holds the hunter's young daughter hostage at gunpoint, and is able to get the hunter to drop his weapon, and give Michael the keys to his Jeep Grand Cherokee. The five escapees board the SUV, presumably en route to a storage room where Michael has some items ready.
Agent Mahone and Captain Bellick use Michael's credit card invoices to find a storage room in Oswego, and each separately rush to the storage facility. It turns out to be a ruse of Michael's, as he is seen in a cemetery storage room, gathering shovels to unearth the ground at the grave of (R.I.P.) E. Chance Woods. Agent Mahone deciphers the message on Michael's tattoo ("Ripe Chance Woods") and arrives at the scene right after the escaped gang of five unearthed Michael's package and put on a fresh set of clothing. Lincoln took the backpack Michael hid and found the brothers' fake passports. The five were able to escape to Oswego and blend in, despite being tailed by Agent Mahone.
Mahone continues to study images of Michael's tattoos and other elements of his escape plan, saying it will tell him everything about where Michael and the others are going, so he can be there waiting for them when they get there.
Elsewhere on the run, T-Bag raids a nearby campground, threatening campers in order to steal a hat and cooler. T-Bag finds the veterinary clinic of Dr. Marvin Gudat, and coerces him to reattach his left hand without the use of anesthesia.
Meanwhile, Dr. Sara Tancredi recovers from her drug overdose. She is interrogated by an FBI agent, who tells her that 7 more prisoners had escaped with Michael. After Nurse Katie Welch's visit, Sara finds an Paper Crane inside her purse. Inside is a message "There's a plan to make all of this right", and a dotted code. The dot code on the origami swan that Sara found can be grouped into lines of numbers. The numbers are 3221243324 for the first line, 4221312231 for the second, and 23133121 for the third.
Veronica discovers yet another secret from Terrence Steadman, whose previous portrayer John Billingsley has been replaced by Jeff Perry. Steadman is being held captive, although somewhat willingly, inside the estate; the doors are locked from the outside, and the windows are bulletproof. Veronica receives a phone call from Lincoln after calling 911, and informs him of what she has learned. While she is on the phone with Lincoln, members of what appears to be The Company arrive and an agent shoots Veronica three times, killing her for finding Terrence Steadman. Hearing the distinctive noise of gunshots after Veronica uttered her final words "Oh my God!", Lincoln slips into grief, as his brother Michael consoles him.
- Manhunt refers to the subject of both the episode and the season as a whole; the state-wide (which quickly becomes nation-wide) manhunt for the Fox River 8.
- Concerning the casting of the second season, William Fichtner is introduced as a new regular cast member, whose character is assigned to track down the eight escapees from Fox River State Penitentiary. This is also the only episode where he is credited as Bill Fichtner.
- The role of Terrence Steadman was recast to Jeff Perry, who replaces John Billingsley as the brother of Caroline Reynolds.
- The series regular cast members who did not appear are Paul Adelstein (who plays Paul Kellerman) and Marshall Allman (who plays L. J. Burrows).
- Despite their roles as two of the eight prison escapees, the two recurring cast members Lane Garrison (who plays David "Tweener" Apolskis) and Silas Weir Mitchell (who plays Charles "Haywire" Patoshik) did not appear in this episode, though they did appear in brief flashbacks at the beginning of the episode.
- "Manhunt" was the first episode of the series to be filmed in Texas after the cast and crew relocated due to the more suitable locations for the impending storyline. The cemetery scene and the following town scene are supposedly set in Oswego, Illinois in the episode. These scenes were actually filmed in McKinney, Texas. While the cemetery scene was filmed at Pecan Grove Cemetery in McKinney, the scene which followed as the fugitives escape into a neighbouring town, was filmed in downtown McKinney.
- Starting with this episode, the blue-tinted graphic used in the first season's commercial bumper which were shots of prison crawlways, is replaced by a sepia-tinted graphic of racing through fields and streets, reflecting the fact that the convicts have become fugitives.
- The premiere of the second season of Prison Break obtained an average of 9.4 million viewers in the United States, down from 10.5 million for the series premiere in August 2005. There was also a decrease of 20 percent in the 18-49 demographic compared to its series premiere, but its household rating grew from a 3.6 to a 3.9 during the last half hour. Australia's Ninemsn reports seemingly less than stellar ratings for the Australian premiere of the second season of Prison Break, "The second season opening of Prison Break attracted 1.2 million viewers, but that was hardly impressive for one of the network's most significant imports."
- This marks the first appearance of Alexander Mahone, who appears in episode after this.
- This marks the last appearance of Robin Tunney as Veronica Donovan.