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.