Blake was born in Yonkers, New York to an African American father Thomas Reynolds Blake and a British mother Betty Blake. He has a brother Thomas, who is also a professional tennis player, and three older half-brothers: Jason, Christopher and Howard, and a half-sister Michelle.

Blake started playing tennis at age five alongside his brother Thomas. When he was 13 he was diagnosed with severe scoliosis and for five years as a teenager he was forced to wear a full-length back brace for 18 hours a day, though not while playing tennis. Blake attended Fairfield High School in Fairfield, Connecticut, where a schoolmate and childhood friend was future musician John Mayer. Blake was inspired to pursue tennis after hearing his role model Arthur Ashe speak to the Harlem Junior Tennis Program. Brian Barker was his first (and longtime) coach. He left Harvard University after his sophomore year to pursue a career in professional tennis.

Blake's style of play is primarily that of an aggressive offensive baseliner. He generally prefers to hit winners from the baseline but his solid net volley and transition game give him an effective all-court game. His forehand (along with Del Potro and Fernando Gonzalez) is considered to be one of the best in the game. However, his one-handed backhand is known to be suspect. Another major strength is his great foot speed. Blake tends to return serves (especially second serves) with great pace, and also makes contact with the ball earlier (on the uprise) when hitting ground strokes. Combined with his relatively flat strokes, these techniques (despite being riskier in terms of making errors) allow him to put more pace on the ball, giving opponents less time to react. Blake likes to take control of points and will usually attempt to hit an outright winner earlier in the rally than many others. He is known as a "shot maker". His go-for-broke style makes him one of the most entertaining players on the tour, though somewhat inconsistent. Since hiring new coach and doubles specialist Kelly Jones, Blake has begun to incorporate more serve and volley play into his game.

At the age of 21, Blake saw his first Davis Cup action in 2001 against India and became the third person of African-American heritage to play for the Davis Cup for the United States (after Arthur Ashe and MaliVai Washington).

Ranked No. 120 in the world, Blake accepted a wild card into AMS Cincinnati. He beat a qualifier and Arnaud Clément to reach the round of 16 where he met Patrick Rafter. Blake came close to winning the first set (falling in a tiebreak), and after dropping the second set, Rafter, according to Blake's autobiography, complimented him at the net and boosted his confidence immeasurably by saying "Now do you believe you can beat someone like me, or even me?"

In January, Blake won the 2002 USTA Waikola Challenger in Hawaii. A month later in Memphis he posted his first win over a top-ten ranked opponent, Tommy Haas, who was then ranked fifth, and reached the finals, losing to Andy Roddick. He reached the quarterfinals at the ATP Masters Series (AMS) event in Rome in May and the finals at Newport in July.

In August, in Cincinnati, he won his first career ATP Tour title and his first ATP Masters Series title: it came in doubles with Todd Martin, making Blake the first African-American male to win a title of any kind in Cincinnati's 101-year history. He was also the first African-American to reach a final in Cincinnati since 1969 when Arthur Ashe reached the doubles finals with Charlie Pasarell. The next week in Washington, he won his first ATP Tour singles title, beating Andre Agassi in the semifinals and Paradorn Srichaphan in the final.

At the U.S. Open, he reached the third round before falling to top-ranked Lleyton Hewitt in five sets.

In 2003 his best results were a quarterfinals at AMS Indian Wells; a Round of 16 finish at the Australian Open, AMS Cincinnati and AMS Miami; a semifinal appearance at San Jose and a finals appearance at Long Island.

While practicing with Robby Ginepri for the Masters event in Rome, he broke his neck when he slipped on the clay and collided with the net post. In July his father died as a result of stomach cancer. At the same time Blake developed shingles, which temporarily paralyzed half his face and blurred his sight.