He is 6' 8" (203 cm) tall, and was born in Belovodsk, Kyrgyzstan, in the former Soviet Union. His younger brother, Wladimir Klitschko, is the current IBF heavyweight champion. Their father was a Soviet Air Force Colonel, and their ethnicity is Ukrainian.

Originally a professional kickboxer, Vitali was also a boxer and won the Super Heavyweight Championship at the first World Military Games in Italy in 1995. He began his professional boxing career in 1996, winning his first 24 fights by either early knockout or technical-knockout (TKO). He and Wladimir were hot prospects, and had signed with the German athlete-promotion company Universum. After moving to Germany and Universum, their charismatic, refined (each holds a Ph.D.) and articulate (they are multilingual) personalities made for mainstream marketability; in time, they became national celebrities in their adopted home country. In his 25th pro fight, on June 26, 1999, Klitschko won the World Boxing Organization Heavyweight Championship from Herbie Hide (of the U.K.) via 2nd-round knockout. He defended the title twice before losing it on April 1, 2000 to American Chris Byrd; complaining of intense shoulder pain, Vitali and his corner decided not to continue the fight after Round Nine. Ironically, Vitali was ahead on all 3 judges' scorecards (89-82, and 88-83 twice), but the way he ended this match brought international criticism, plus a reputation as a quitter. Some gave him the nickname "Quitschko". He had surgery to repair the rotator cuff torn during the bout. In Byrd's next fight he was dethroned by Wladimir (knocking Byrd down in Rounds 9 and 11), avenging his elder brother.

Though saddled with this new reputation, Vitali continued to fight his way up the ladder of contenders, beating Orlin Norris, Ross Puritty, Vaughn Bean, and Larry Donald. On June 21, 2003, he fought Lennox Lewis for his WBC Heavyweight Championship in Los Angeles. For the first two rounds, Vitali dominated the fight against Lewis. In Round Three, Lewis landed a punch that left a gruesome cut over Klitschko's left eye. The next 3 rounds were give and take; after Round Six, all 3 judges' scorecards read 58-56 in favor of Klitschko. Before Round Seven, the ringside doctor inspected the cut and thought it severe enough to threaten eye damage if hit again. He stopped the fight, despite Klitschko's pleas to continue it (wanting to beat Lewis in the ring). In a cruel twist of fate, California's boxing regulations at the time stated that the winner had to be the opponent who was medically approved to continue -- in this case, Lewis. Though he had lost on a technicality, Klitschko gained international respect for essentially outboxing the consensus World Heavyweight Champion. Afterward, it was revealed that Vitali had kept fighting despite sustaining an internal injury, as well. This redeemed him in most fans' eyes, and many no longer considered him a quitter. Even more, many people and media started calling him "the People's Champion".

On December 6, 2003, Vitali returned to the ring against Canadian Kirk Johnson in Madison Square Garden and knocked him out in Round Two, reclaiming his place as the WBC's number-one contender. Around this time, the Klitschkos moved from Berlin to L.A. The western U.S.'s premium training facilities were now nearby, and they could boost their profiles by mixing socially with boxing insiders. In January 2004, they notified Universum that they would not re-sign when their contracts expired in April. Universum sued the brothers, arguing that their recent injuries had triggered a clause binding them beyond April. The suit was resolved in late 2004.

Klitschko earned an 8th-round TKO victory over South African Corrie Sanders on April 24, 2004, to capture the World Boxing Council Heavyweight Championship which had been vacated by Lewis, in Los Angeles. Sanders had dominantly knocked-out (2nd Round) younger brother Wladimir on March 8, 2003. This fight was also for The Ring Magazine belt. Despite the bout with Vitali being for the "legitimate" World Title, few had seen Sanders as a legitimate contender for the crown before his bout with Wladimir (who had himself been the Top Contender). Klitschko was rocked early by the powerful Sanders, but by using movement and strong punching he broke down Sanders and forced the referee to stop the bout. In a sport flooded with under-educated competitors, the former Soviet became the first professional boxing world champion with a PhD (in sports medicine and philosophy).

Vitali Klitschko's first world title defense was against British contender Danny Williams. Williams had become suddenly marketable from a surprise K.O. of the declining "Iron" Mike Tyson. Klitschko TKO'd Williams in 8 rounds on December 11, 2004 while wearing an orange cloth to show support for the Ukrainian presidential opposition movement. Klitschko easily threw many punches during the fight, knocking Williams down in the 1st, 3rd, 7th, and 8th rounds before the fight was mercifully stopped. Immediately afterwards, Klitschko dedicated his victory to democracy in his native Ukraine, and also to the Ukrainian presidential candidate Viktor Yushchenko, whom he supported in the December 26, 2004 election revote.

The WBC designated former WBC & IBF world Heavyweight Champion Hasim Rahman as Klitschko's next mandatory challenger; the fight was set for April 30, 2005. Klitschko injured his thigh while training for the fight, so it was rescheduled for June 18. As this date approached, Klitschko's camp said that the thigh had not fully healed; the WBC made July 23 the new fight date. Soon after this second postponement, Vitali's doctors reportedly discovered back injuries that they said demanded minor-yet-immediate corrective surgery. The WBC pushed the fight date back to November 12; Vitali's share of the purse following this match would reportedly be between $7.8 million and $10 million (U.S.). After this third rescheduling, Rahman, tired of the delays, fought the #2 contender over the summer for the WBC's "Interim" heavyweight title (i.e., temporary-champion status, pending the linear titleholder's Klitschko's return; then, the two must fight each other). Rahman won the 'championship;' Vitali would be stripped of his now-disputed title if his first fight back was not against Rahman, or if he was not ready to fight by the WBC's deadline. During the first part of the week of November 12, 2005, Klitschko had major surgery in L.A. for right knee injuries (a torn meniscus, a bone bruise, plus an undiagnosed MCL tear) that occurred while training the week before. The total recovery time from such injuries averaged around 6 months. The WBC said it would strip him of the championship if he was unable to box within 60-90 days of a soon-to-be-announced base date. However, on November 9, 2005, Vitali Klitschko announced his retirement from professional boxing. He cited regrets about his suddenly-mounting injuries, a desire to leave the sport while still on top, and political aspirations in his home country of Ukraine.