Lysacek is of Italian and Czech descent; his great-grandfather František Lysáček emigrated from Czechoslovakia to Chicago in 1925. He is a Greek Orthodox Christian, having stated that one of his most prized possessions is his Orthodox cross. He wears Graf figure skating boots.

In 1996, Lysacek won the U.S. national title at the Juvenile level – the lowest qualifying level in the U.S. Figure Skating competition structure. In 1997, he moved up to Intermediate and won the pewter medal (fourth place) at the Junior Olympics, after winning both his regional and his sectional qualifying competitions. After failing to qualify for Nationals on the novice level in 1998, Lysacek won the U.S. Novice title at the 1999 U.S. Championships at the age of thirteen.

In the 1999–2000 season, Lysacek made his international junior debut and competed on the 1999–2000 ISU Junior Grand Prix circuit. He placed seventh at his first event and then won his second event. He was the third alternate to the 1999–2000 ISU Junior Grand Prix Final.

Lysacek had a strong showing in the 2000–2001 season. He competed in his second season on the Junior Grand Prix circuit and won two silver medals. He was the 7th qualifier for the 2000–2001 Junior Grand Prix Final and placed 8th at the Final.

Over the next season, Lysacek dealt with several injuries, including broken ribs, which resulted in lost training time. After the September 11, 2001 attacks, the United States Figure Skating Association cancelled the 2001–2002 ISU Junior Grand Prix event to be held in Arizona and did not allow its junior skaters to compete on the Junior Grand Prix circuit for the rest of that season. At the 2002 U.S. Championships, Lysacek repeated his 12th-place finish from the previous year and was not selected for the team to the 2002 World Junior Championships. He was sent to the 2002 Triglav Trophy in April, where he won the gold medal on the junior level.

After that, Lysacek changed his diet and his training habits. In the 2002–2003 season, he competed on the 2002–2003 ISU Junior Grand Prix circuit and won two silver medals. He was the 4th qualifier for the 2002–2003 Junior Grand Prix Final, where he placed 5th. For the 2003 U.S. Championships, his goal had been to place in the top ten. He achieved this with a 7th-place finish.

Evan Lysacek was originally coached by Candice Brown in Naperville. After that, he worked with Deborah Stoery in Naperville, Illinois and Addison, Illinois for three years. For the next two years, he had an arrangement where he would train under both Addison-based Maria Jeżak-Athey and Moscow-based Viktor Kudriavtsev. Kudriavtsev would come to Chicago for part of the year to coach, and Lysacek spent his summers at Kudriavtsev's summer training camps in Moscow, Russia and Flims, Switzerland. When that arrangement proved untenable, Kudriavtsev recommended Lysacek to Carroll, who agreed to coach Lysacek on the condition that Lysacek would work more with Congemi than with himself, due to Carroll's commitments to Timothy Goebel. Lysacek moved to El Segundo, California to work with Frank Carroll and Ken Congemi in June 2003. Lysacek worked with both Congemi and Carroll through the 2006-2007 season, after which he began working solely with Carroll. He has also trained with ballerina Galina Barinova.

In the 2004–2005 season, having aged out of the junior level at age 19, Evan Lysacek made his senior international debut. Skating through a hip injury, Lysacek placed fifth at the 2004 Skate America, the first Grand Prix event of his career. He repeated that placement a few weeks later at the 2004 Cup of Russia. At the 2005 U.S. Championships, Lysacek won the bronze medal after receiving the only 6.0 of his career for his short program. He went on to win his first senior international title at the 2005 Four Continents. He competed next at the 2005 World Championships in Moscow. There, he won a surprising bronze medal at his first senior World Championships, a competition for which his goal had been only to qualify for the free skate.

In the 2005–2006 season, Lysacek again competed on the Grand Prix. He placed second at the 2005 Skate America, but it was clear that his Grease free skate was not working. Lysacek and coach Frank Carroll made the decision to find a new long program. Lysacek's new Carmen program was a success at the 2005 NHK Trophy, where Lysacek placed second. Lysacek was the only American man to qualify for the 2005–2006 Grand Prix Final, but he withdrew before the event because of bursitis and tendinitis in his right hip.

In the 2006–2007 season, Lysacek placed second at the 2006 Skate America. Two weeks later, Lysacek won the gold medal at the 2006 Cup of China by a 20-point margin. He was the fourth qualifier for the 2006–2007 Grand Prix Final in his second consecutive year in qualifying for the event. However, he withdrew from the competition before he was to skate his short program due to an injury to his hip.

Lysacek has worked with many choreographers over the years, including Oleg Epstein and Kurt Browning. Both his programs for the 2007–2008 season were choreographed by Lori Nichol. He worked with Tatiana Tarasova on his programs for the 2008–2009 season. He returned to Nichol for the 2009–2010 season.

Lysacek began the 2008–2009 season at the 2008 Skate America, where he won the bronze medal. The following week, he competed at the 2008 Skate Canada International, where he won a second bronze medal. Lysacek was the second alternate for the 2008–2009 Grand Prix Final.

In the past, Lysacek has worn costumes designed by Christian Dior, Gianfranco Ferre, Alexander McQueen, and Vera Wang, American fashion designer and former figure skater. Wang created the mock tuxedo Lysacek wore when he won the 2009 World Championships. Lysacek and Wang also collaborated to design his costumes for the 2010 Winter Olympics, as well as those worn for the rest of the 2009–2010 season.

Lysacek was a Celebrity contestant on Dancing with the Stars for the tenth season, which premiered on Monday, March 22, 2010. He and his professional dance partner Anna Trebunskaya made it to the finals and finished in second place to Nicole Scherzinger and Derek Hough.

In June 2011, he received two Grand Prix assignments for the 2011–2012 season – 2011 Skate America and 2011 Trophée Eric Bompard. He resumed training with Frank Carroll at Lake Arrowhead, California, and his publicist said he would make a decision whether to compete later in the summer. In September, he announced that his goal was to participate in the 2014 Winter Olympics. In October, U.S. Figure Skating announced that he would not compete at the 2011 Skate America due to a financial disagreement, and Lysacek confirmed that he would not take part in the Grand Prix series, explaining on his Twitter that "a suitable agreement could not be reached between U.S. Figure Skating and myself by the event entry deadline". In November, Lysacek confirmed he would not enter the 2012 U.S. Championships in January 2012 but negotiations with U.S. Figure Skating continued.

In April 2012, the U.S. Department of State's Bureau of Educational and Cultural Affairs named Lysacek a Sports Envoy.

Lysacek supports a number of charities. He participated in Target – A Time for Heroes, a Celebrity charity event benefiting the Elizabeth Glaser Pediatric AIDS Foundation. He also supports the Dana-Farber Cancer Institute (Jimmy Fund). He began supporting Figure Skating in Harlem in 2006 and is a board member of the charity. Lysacek has attended their benefit gala in New York City regularly.

On August 30, 2014, during a TV interview, Lysacek mentioned his competitive skating career was coming to an end.

On December 15, 2015, U.S. Figure Skating announced Lysacek would be a member of the U.S. Figure Skating Hall of Fame Class of 2016. The induction ceremony was held on January 22, 2016 at the 2016 U.S. Figure Skating Championships.