Alongside his acting career, Nichols maintains a strong interest in cinema.
He keeps a log of every film he sees, "I take it to the movies and write down who does the music, edits, directs, and how long the film is." He was previously in a relationship with One Tree Hill co-star Sophia Bush, and took the role of Julian Baker in the series to be closer to her.
In 2007, Nichols appeared in a few episodes of the NBC drama series Friday Night Lights, before being cast as Julian Baker in The CW's teen drama One Tree Hill.
He played the disturbed Roderick Usher, who was described by Nichols as a "twisted, terminally ill, fucked-up guy".He starred as John Monad in the HBO drama series John from Cincinnati, and portrayed Spencer Monroe in the AMC horror drama series The Walking Dead.Nichols initially wished to attend the University of Texas, but moved to Los Angeles after his signing and enrolled at the University of Southern California, graduating in 2002 with a Bachelor of Arts degree in English.Nichols has been friends with actor Jake Gyllenhaal since the two met on the set of The Day After Tomorrow in 2004.Nichols said in one interview, "I've learned a ton from Jake. He told me everything about acting, the business, girls, life." In the early morning of August 24, 2007, Nichols was pulled over in Jackson, Michigan after driving the wrong way down a one-way street in his silver Mercury Mountaineer.“Everybody has moments when they look at their partner and wonder, Could this person be my person?But I believe that the more you experience, the more your feelings begin to exist in shades of gray,” Bush wrote.The film received negative reviews but was a box office success.For the role, Nichols had to learn tennis from scratch; he was trained to look professional by Pat Cash, who was taken aback by Nichols' skill. He's our star pupil." Glory Road, directed by James Gartner and starring Josh Lucas, is a film based on the true story of the 1966 NCAA Men's Division I Basketball Championship, in which Coach Don Haskins led a team with an all-black starting lineup, a first in NCAA history.Although Nichols had guest appearances in Sliders, Odd Man Out, CSI: Crime Scene Investigation, Family Law, Watching Ellie, and Wolf Lake before his graduation, his big break came in 2002 when he appeared as Brenda Chenowith's lover in two episodes of Six Feet Under.He had previously appeared in two films, Durango Kids in 1999 and Holiday in the Sun in 2001.