At the Shanghai Masters, Nishikori reached his first Masters 1000 semifinal. He defeated Robin Haase, fourth seed Jo-Wilfried Tsonga, and Santiago Giraldo, in the first three rounds. In the quarterfinals, Nishikori upset 12th-seeded Alexandr Dolgopolov in straight sets. He lost to No. 2 Andy Murray in his first Masters 1000 semifinal. He reached a career-high of world No. 30, breaking the previous Japanese mark of No. 46, set by Shuzo Matsuoka in July 1992.

Nishikori was born in Matsue in Shimane Prefecture, Japan. His father, Kiyoshi, is an engineer, and his mother, Eri, is a piano teacher. He has an older sister, Reina, who graduated from college and works in Tokyo. He began playing tennis at the age of five. He first won the All Japan Tennis Championships for Kids in 2001, and graduated from Aomori-Yamada High School. Nishikori moved to Bradenton, Florida to join the IMG Academy in 2004 at 14 years of age. His pastimes include football, golf, reading, and listening to music. Nishikori was previously coached by Brad Gilbert. Dante Bottini is his current coach since December 2010. Former world No. 2 Michael Chang was added to his coaching team from January 2014.

As a junior, he compiled a 73–37 win/loss record in singles and 53–31 in doubles, achieving a combined ranking of No. 7 in the world in July 2006.

Nishikori lost in the first round of the Miami Masters to the Spanish player Albert Montañés. He faced James Blake again, this time at the River Oaks International tournament in Houston, Texas in the first round, but Kei lost in two sets. He went out in the third round of the 2008 Queen’s Club Championships against Rafael Nadal in just over two hours. Facing the world No. 2, Nishikori played well in the match and showed promise. His first Grand Slam appearance at the 2008 Wimbledon Championships on 23 June 2008 ended in a first-round forfeiture to French player Marc Gicquel. Suffering from an abdominal muscle strain, Nishikori retired after the second set. In August, he entered the Beijing Olympics on a wildcard. There, he lost in the first round to Rainer Schüttler of Germany.

Nishikori made his debut at the US Open, defeating 29th seeded Juan Mónaco in the first round. He cruised to the third round, after downing Croatian Roko Karanušić. On 30 August 2008, he became the first Japanese player to reach the round of 16 at the US Open in 71 years, when he beat fourth seed David Ferrer in five sets in what was considered one of the tournament’s major upsets. He lost his chance, however, to compete in the quarterfinals when he was beaten by 17th seed Juan Martín del Potro in straight sets.

Nishikori made his Davis Cup debut for Japan in April 2008 in the Asia/Oceania Zone Group I semifinal against India in New Delhi. He was 18 years and 104 days old, the youngest player to play for Japan. He played the singles rubber on the first day, but lost to Rohan Bopanna in five sets. He then defeated Mahesh Bhupathi in a dead rubber to record his first Davis Cup match win. To date, Nishikori has compiled a 19–3 win/loss record overall (17–3 in singles and 2–0 in doubles).

Nishikori represented Japan at his maiden Olympics in Beijing 2008. He competed in the singles competition from ITF places spot. There, he lost in the first round to Rainer Schüttler of Germany in three sets.

Nishikori and Ferrer have met 14 times, with Nishikori leading 10–4. They met for the first time in the 2008 US Open with Nishikori registering his first win over a top-10 player, beating David Ferrer in a five-set thriller as a teenager. They next met again from 2011 to 2013 with Ferrer winning 3 times in straight sets and Nishikori winning only once in the Olympics at 2012 in three sets. However, in 2014, Nishikori showed that his 2–3 deficit head-to-head encounter against Ferrer was just the beginning and thrashed the Spaniard in each of the 4 encounters in 2014. They first met in 2014 in the Miami Masters with Nishikori beating Ferrer in 3 tight-sets after saving 4 match points to progress to the QF. They next had an epic encounter at the Madrid Open with Nishikori beating Ferrer in another tight 3-setter to progress to the final of a Masters 1000 for the first time in his career. Their next 2 encounters were in the BNP Paribas Masters and the ATP World Tour Finals where Nishikori again defeated the Spaniard in 3 sets.

Nishikori and Cilic have met 16 times, with Nishikori leading 10–6. Cilic won their first ATP World Tour meeting in 2008 at Indian Wells, beating Nishikori in straight sets in the first round. In 2010, Nishikori avenged that loss at the US Open, beating Cilic in a tough five-setter lasting almost five hours. In 2011, they met at the Chennai Open where Nishikori beat Cilic in three sets. In 2012, they encountered each other at the US Open where Cilic avenged his past US Open loss to Nishikori by beating him in four sets to progress to the 4R. In 2013, they met at the Memphis Open where Nishikori beat him in straight sets to progress to the SF and he would later go on to win the title.

Kei made his comeback after his injury of the previous year. After receiving a wildcard at Delray Beach, he was beaten in the first round by Benjamin Becker. Kei returned to the Challenger tour later in April with great success, reaching quarterfinals at both Baton Rouge and Tallahassee events, followed by a victory at the Savannah Challenger over Ryan Sweeting in the final. On 15 May 2010, he won the Sarasota open by defeating Brian Dabul, in three sets.

At the U.S. Open, the Japanese No. 1 met Marin Čilić in the second round. Nishikori ousted the 11th seed in 5 sets to advance to the third round, his best Grand Slam tournament showing in 2010.

In the 2011 Australian Open, Nishikori reached the third round, defeating Fabio Fognini and Florian Mayer along the way. His run was ended in the third round by ninth seed Fernando Verdasco. After the third-round appearance in Melbourne, his ranking rose to No. 70.

He wears Uniqlo clothing and as of the beginning of 2017 red Nike Vapor Tour shoes after having played for almost a decade in Adidas. He is also sponsored by Nissin Foods, TAG Heuer, Fast Retailing, LVMH Moët Hennessy, Japanese financial services firm Jaccs Co., WOWOW, mattress topper Air Weave, EA Games, Delta Air Lines and Japan Airlines, in a deal which has his image emblazoned on a Boeing 777-300ER dubbed “JET-KEI”. He is often seen wearing a Cup Noodles badge on his sleeve during matches. In 2011, he filmed a commercial for Morinaga & Company’s sports drink Weider in Jelly. He also carries around a character called Mr. Saturn from the popular video game Mother / Earthbound.

Nishikori and Wawrinka have met 9 times, with Nishikori trailing 4–5. Wawrinka won both of their first two meetings in 2012, in the 3rd Round of Cincinnati Masters and in the quarterfinal of Buenos Aires respectively. Nishikori recorded his first win against Wawrinka at the quarterfinal of the 2014 US Open in a thrilling tight five-sets match which saw Nishikori later became the eventual finalist of the tournament.

Nishikori and Raonic have met 7 times, with Nishikori leading their head-to-head 5–2. They met once in 2012, 4 times in 2014 and twice during the 2015 season. At their first meeting in the 2012 Rakuten Japan Open final, Nishikori won it in 3 sets. Their first meeting in 2014 was at the Madrid Masters with Nishikori winning in two tiebreak sets. In Wimbledon 2014 4R, Raonic scored his first win against Nishikori beating him in four sets to advance to the quarterfinals. They met again in the US Open 4R where the match tied the all-time latest finish for a match at the US Open with Nishikori prevailing in five tight-sets which lasted 4 hours and 19 minutes. They had a rematch of their 2012 final in the Rakuten Japan Open 2014 final where Nishikori won again in 3 sets.

Nishikori has endorsed the Wilson Wilson Burn 95; however, it is believed by racquet enthusiasts that he used an older modified Wilson nCode nTour underneath the Steam paint job. In the past, special versions of the Steam racquet have been sold by Wilson, exclusively in Japan, capitalizing on Nishikori’s popularity in his home country. Most recently, in 2012 the Steam Pro was available for sale, and was advertised as having the same specifications as Nishikori’s actual racquet.

In 2013 US Open first round, Nishikori lost to a lower-ranked opponent, this time to world No. 179 Dan Evans in straight sets.

Michael Chang became Kei Nishikori’s coach in 2014.

Nishikori began his clay-court season at the 2015 Barcelona Open Banc Sabadell where he reached the final after beating Teymuraz Gabashvili, Santiago Giraldo, Roberto Bautista Agut and Martin Kližan. He successfully defended his title by beating Pablo Andújar in the final in two sets to win his ninth career title on the tour. At the 2015 Mutua Madrid Open, Nishikori was granted a first-round bye and proceeded by defeating David Goffin in three tough-sets in the second round. He reached the semifinals after beating Roberto Bautista Agut and David Ferrer in straight sets respectively. He then lost to Andy Murray in the semifinals, and his ranking dropped to 6th as a result of failing to defend his points from the final in 2014.

In the 2014 Davis Cup World Group first round in Tokyo, Japan defeated Canada 4–1, and Nishikori had a hand in three Japan victories in the tie. He beat Peter Polansky and Frank Dancevic in the singles rubbers, and teamed up with Yasutaka Uchiyama for a victory in doubles over Dancevic and Daniel Nestor. Japan advanced to the quarterfinals in the World Group for the first time, but Nishikori missed the quarterfinal against Czech Republic due to a left groin injury.

In 2014, their rivalry was more intense with 3 ATP meetings. They first met in 2014 at the Brisbane International where Nishikori beat him in three sets to book his semifinal spot. They met again at the clay courts of the Barcelona Open where Nishikori dominated Cilic in another straight sets victory where he would later go on to win his first title on clay. Their most significant meeting would be at the 2014 US Open, they met in the finals after Nishikori overpowered world No. 1 Novak Djokovic and Cilic overcame world No. 2 Roger Federer in the semifinals. Their meeting in the final made the 2014 US Open the first Grand Slam where none of Federer, Nadal and Djokovic reached the final since the 2005 Australian Open. However, Nishikori was defeated in straight sets by an in-form Marin Cilic in the final.

Nishikori began the 2015 season by participating in the 2015 Brisbane International and reached the semifinals before being beaten by Milos Raonic in 3 tight-set tiebreaks. He reached the 2015 Brisbane International doubles finals with his partner Alexandr Dolgopolov but lost in straight sets. Nishikori equalled his best record yet in the Australian Open by reaching the quarterfinals for the second time in his career, dropping only 2 sets along the way, but he was beaten in straight sets by defending champion Stan Wawrinka. In February, Nishikori won his eighth singles title and became the first ever player to win the Memphis Open three times in a row, beating Kevin Anderson in straight sets in the final.

He next participated in the 2015 Abierto Mexicano Telcel and reached the final, losing only a set to Kevin Anderson in the semifinals. By reaching the final, he earned enough ATP ranking points to move into a new career high world ranking of No. 4. However, he lost to David Ferrer in straight sets in the final. During the March Masters, he reached the fourth round of the 2015 BNP Paribas Open for the first time in seven appearances but was upset by Feliciano López in straight sets in the fourth round. In the 2015 Miami Open, he defeated Mikhail Youzhny, Viktor Troicki and David Goffin all in straight sets losing only a total of 10 games to reach the quarterfinals. However, he was upset by an in-form John Isner in straight sets.

In 2015, the duo first met at the Brisbane International with Raonic prevailing in 3 tight-set tiebreaks. This was followed later on in the same year in the Davis Cup where Nishikori won in another epic five-setter to keep Japan’s hopes for a quarterfinal place alive with the score tied again at 2–2.

In 2015, Ferrer had a remarkable start to the season but was beaten in the Australian Open by Nishikori in a dominant straight sets victory. However, Ferrer ended his losing streak to Nishikori in the Abierto Mexicano Telcel where he beat Nishikori in straight sets in the final. In Madrid, in the quarterfinals, Nishikori took revenge and beat him in straight sets.

In 2015, the pair met in the semifinals of the 2015 Citi Open, with Nishikori coming back from a set down to prevail in three, and gain a place in his 15th career final. They meet again later on in the 2015 Japan Open where Nishikori came back from a set down to defeat Cilic in three tight sets. In 2016, the duo met in the 4th round of the 2016 Wimbledon where Nishikori retired mid-match in the 2nd set after losing the first set due to a rib injury which had disrupted his grass season. They met again in the final of the Swiss Indoors, where Cilic prevailed in straight sets. During the round-robin stage of the Year-End 2016 ATP World Tour Finals, Cilic came from a set down to defeat Nishikori and ultimately prevail. Most recently, Nishikori defeated Cilic in the quarterfinals of the Monte-Carlo Masters by a score of 6–4, 6–7, 6–3.

From the 2015 to the 2018 season, Nishikori used the Wilson Burn 95.

With Murray, Federer and Nadal absent, Nishikori was seeded 3rd for the Rogers Cup Masters in Toronto. After beating Grigor Dimitrov and Stan Wawrinka in the quarterfinals and semifinals respectively, Nishikori then lost to Djokovic in straight sets in the finals, going 0–5 so far in the season against the Serb. Nishikori then participated in the 2016 Summer Olympics, where he reached the semis before being defeated by World No. 2 Andy Murray in straight sets. However, he later acquired the bronze medal after he defeated Rafael Nadal 6–2, 6–7 (1), 6–3, becoming the first Japanese man to win an Olympic tennis medal since Ichiya Kumagae in the 1920 Summer Olympics.

They met 3 times in 2016. Nishikori won 2 of their 3 meetings in 2016. They both qualified for the 2016 ATP World Tour Finals and were drawn in the same group. Nishikori defeated Wawrinka in the round robin match.

At the 2018 US Open, Nishikori and Cilic again met in the quarterfinals. In a five set thriller, Nishikori won a spot in the semifinal of the US Open for only the third time (and only the third time advancing past the quarters in any of the four majors).

As of 2019, after the dismissal of the Burn line, Nishikori currently endorses the Wilson Ultra 95.

In August 2020, not having played since the 2019 US Open due to injury and the coronavirus pandemic, Nishikori (twice) tested positive for COVID-19.