Ishikawa attended Federal Way High School in Federal Way, Washington, where he lettered in baseball, leading his team to the Washington State Class 4A Title as a junior in 2001 and to the title game as a senior in 2002. He was drafted in the 21st round of the 2002 draft by the San Francisco Giants. The Giants gave him a $955,000 bonus to prevent him from attending Oregon State University. The bonus was at the time the highest for a non-first-round player, cued on by the organization’s approaching signing deadline. The Giants could afford to pay a 21st-round pick that much because their higher picks had signed quickly for routine bonuses.

Ishikawa began his career playing for the rookie-league Arizona League Giants in 2002. He batted .279 with 10 runs scored, 19 hits, one home run and 10 Runs batted in (RBI) in 19 games (68 at-bats) before being called up to the Class A Short Season Salem-Keizer Volcanoes of the Northwest League. With Salem-Keizer, he hit .307 with 14 runs scored, 27 hits, one home run, and 17 RBI in 23 games (96 at-bats). His performance helped Salem-Keizer win the Northwest League championship.

In 2003, Ishikawa was initially assigned to the Class A Hagerstown Suns of the South Atlantic League. After he batted .206 with 20 runs scored, 40 hits, three home runs, and 22 RBI in 57 games (194 at-bats), he was demoted to Salem-Keizer. In 66 games (248 at-bats) with the Volcanoes, he batted .254 with 53 runs scored, 63 hits, three home runs, and 31 RBI.

Coming into 2004, Ishikawa was ranked the Giants’ seventh-best prospect by Baseball America. He spent most of 2004 with the Suns, batting .257 with 59 runs scored, 92 hits, and 54 RBI in 97 games (355 at-bats). He tied with Nate Schierholtz for the team lead with 15 home runs, and he won the Hagerstown Player of the Month award in July. In the last month of the season, Ishikawa was promoted to the Class A-Advanced San Jose Giants of the California League, where he batted .232 with 10 runs scored, 13 hits, one home run, and 10 RBI in 16 games (56 at-bats). He also played eight playoff games for San Jose.

Ishikawa was ranked the 10th-best prospect in the Giants’ organization by Baseball America entering 2005. In 2005, he spent the entire season with San Jose. In 127 games (432 at-bats), he batted .282 with 87 runs scored, 122 hits, and 79 RBI. His 22 home runs ranked fourth in the San Francisco Giants’ organization and tied with Bryan LaHair, Travis Metcalf, and Aneudi Cuevas for seventh in the California League. He appeared in six playoff games, batting .217 with four RBI as San Jose won the California League championship.

Ishikawa attended spring training with the Giants in 2007 but was reassigned to the minors on March 6. He spent the entire season in the minors, splitting time between Connecticut and San Jose. He began the season with Connecticut, hitting .214 with three home runs and 17 RBI in 48 games (173 at-bats) before suffering a knee injury. He was sent to San Jose on June 28 to recover from it, and he said that the Giants told him he would be promoted to Triple-A after a rehab assignment. However, he struggled and remained with San Jose for the rest of the year, batting .268 with 13 home runs, 34 RBI, and a .551 slugging percentage in 56 games (198 at-bats). He batted .241, hit two home runs, and posted five RBI in the playoffs as San Jose won another California League championship.

Ishikawa met his wife, Rochelle, a dental assistant, after being hit by a pitch in the face in his first game with San Jose. They married in 2007 and have three children, including a daughter who was born on Ishikawa’s 25th birthday in 2008. Ishikawa became a Christian in 2007, which he believes helped him out of his slump that year. He says, “Faith will always be the biggest part of anything that happens.”

In 2008, Ishikawa again attended spring training for the Giants and again began the season in the minors. On August 13, he was called up by the Giants to replace a slumping John Bowker as the Giants’ starting first baseman, a position Ishikawa held for most of the remainder of the season. Ishikawa hit his first major league home run on August 17 at Turner Field, a two run shot off Charlie Morton to right field in a 3–1 victory over the Atlanta Braves. He set a career high by having three hits on September 12 and 14 against the San Diego Padres. In 33 games (95 at-bats) with the Giants, Ishikawa batted .274 with 12 runs, 26 hits, six doubles, three home runs, and 15 RBI.

Ishikawa retained the position of starting first baseman in 2009. In the first game of the season, Ishikawa had two hits, including a three-RBI triple in the first inning against Milwaukee Brewers’ starting pitcher Jeff Suppan as the Giants won 10–6. From May 25 through July 11, Ishikawa had his best stretch of the year, batting .326 while hitting seven home runs and driving in 17 runs. He set a career high with four hits on May 25 and hit his first home run of the year, a three-run shot against Buddy Carlyle, in an 8–2 victory over Atlanta. On July 3, he hit a ball that was originally ruled a double against Felipe Paulino, but the umpires changed it to a three-run home run after watching the replay as the Giants won 13–0 over the Houston Astros. Ishikawa and Juan Uribe hit the Giants’ first set of back-to-back home runs in 2009 against Josh Geer on July 9 in a 9–3 victory over the Padres. Through July 26, he batted .269 with seven home runs and 30 RBI. On July 27, the Giants traded for Ryan Garko from the Cleveland Indians, intending for him to replace Ishikawa at first base and provide more offense than Ishikawa had. However, Garko struggled to produce offensively, and at the end of August Ishikawa began making most of the starts at first for the rest of the year. On August 25, he snapped a 2–2 tie with a game-winning three-run eighth-inning home run against Jon Rauch as the Giants defeated Arizona 5–4. In 120 games (326 at-bats), Ishikawa batted .261 with 49 runs scored, 85 hits, 10 doubles, nine home runs, and 39 RBI. His batting average at AT&T Park was fifth in the National League (NL) for home stadiums at .349, but he batted .162 in away games. Defensively, his .996 fielding percentage was third in the NL behind Adam LaRoche’s .999 and Todd Helton’s .998.

After the final game of spring training in 2011, Ishikawa was designated for assignment and outrighted to the minors to make room for rookie first baseman Brandon Belt. On April 24, Ishikawa hit a grand slam for Fresno against Kevin Mulvey in a 12-5 victory over the Reno Aces. He did not appear for the Giants in 2011, spending the season with the Grizzlies until he injured his shoulder diving for a ball early in the year and underwent season-ending shoulder surgery in the summer of 2011. In 56 games (175 at-bats) for the Grizzlies, Ishikawa batted .251 with 21 runs scored, 44 hits, 14 doubles, three home runs, and 18 RBI. On November 2, the Giants made him a free agent.

Ishikawa signed a minor league contract with the Milwaukee Brewers on December 12, 2011, and made the team out of spring training as a backup first baseman and pinch hitter. On May 2, he became the starting first baseman for the Brewers after Mat Gamel tore his anterior cruciate ligament. He hit two home runs against Dillon Gee and had five RBI on May 15 in an 8–0 win over the New York Mets. He batted .250 with four home runs and 14 RBI in his first 32 games before going on the disabled list on May 27 with a left rib-cage strain. He returned from the disabled list on June 23, but by then Corey Hart had taken over the first base job, limiting Ishikawa to a reserve role for the rest of the year. On October 3, the final game of the season, Ishikawa had four RBI against Andrew Werner in a 7–6 loss to the Padres. In 94 games (152 at-bats), he hit .257 with four home runs and 30 RBI. On November 3, Ishikawa elected to become a free agent after being outrighted off the Brewers’ 40-man roster the day before.

On December 19, 2012, Ishikawa signed a minor league contract with the Baltimore Orioles. He spent most of spring training with the team but was assigned to the Triple-A Norfolk Tides of the International League on March 27. In 49 games (177 at-bats) with Norfolk, he batted .316 with 56 hits, seven home runs, and 31 RBI. Ishikawa was brought up from the Tides on June 18 when pitcher Miguel González was placed on the paternity leave list; Ishikawa was called up to play designated hitter and give Chris Davis days off at first base. Ishikawa appeared in six games for the Orioles, getting two hits in 17 at-bats with 1 RBI. The Orioles designated him for assignment on June 29 to make room for Jair Jurrjens on the roster.

On July 18, 2013, Ishikawa signed a minor league deal with the Chicago White Sox and was assigned to the Charlotte Knights of the International League. In 34 games with the Knights (120 at-bats), he batted .250 with 30 hits, two home runs, and 23 RBI. His combined totals between Norfolk and Charlotte were a .290 batting average, 86 hits, nine home runs, and 54 RBI in 83 games (297 at-bats). Only able to see his family for 14 days between February and September, Ishikawa considered retirement.

After Ishikawa decided to play for one more season, the Pittsburgh Pirates signed him to a minor league contract. After prospect Andrew Lambo struggled in 2014 spring training, Ishikawa made the Pirates’ roster. He started on Opening Day (March 31) and platooned at first base with Gaby Sánchez, with Ishikawa playing against right-hander and Sánchez playing against left-handers.

In the 2014 National League Championship Series, Ishikawa batted 5-for-13 (.385) with 7 RBIs. He recorded the game-winning RBI in Game 1 and drove in three runs via a bases-loaded double in Game 3. In Game 5, with the Giants leading the series three games to one, Ishikawa hit a 3-run walk-off home run in the bottom of the ninth inning off of St. Louis Cardinals pitcher Michael Wacha to clinch the pennant for the Giants and their third World Series appearance in the past five seasons. Ishikawa’s home run was the first to send a National League team to the World Series since Bobby Thomson’s Shot Heard ‘Round the World in 1951. Ishikawa’s home run was the first ever to end an NLCS and the fourth to end any LCS, after Chris Chambliss (1976 ALCS), Aaron Boone (2003 ALCS), and Magglio Ordonez (2006 ALCS).

On December 4, 2014, Ishikawa and the Giants agreed to a one-year, $1.1 million contract for 2015. He started the 2015 season on the disabled list due to a back injury suffered near the end of spring training. At the conclusion of his rehab assignment, he was designated for assignment by the Giants and removed from the 40-man roster. Ishikawa subsequently cleared waivers and was sent to the Sacramento River Cats. On June 24, 2015, Ishikawa was called back up to the Giants to take the place of the injured Nori Aoki. He was designated for assignment again on July 3.

Ishikawa was claimed off waivers by the Pirates on July 5, 2015. In 38 games with the Pirates, Ishikawa hit .224 with one home run and 8 RBI.

In January 2016, Ishikawa was reportedly close to signing a minor-league contract with the Seattle Mariners, but the deal fell through. He signed a minor-league contract with the Chicago White Sox on February 9. He opened the 2016 season with the Triple-A Charlotte Knights. He was released on May 24, 2016. On June 8th, Ishikawa signed a minor league deal to return to the San Francisco Giants organization, but was granted free agency in November.

On March 16, 2018, Ishikawa rejoined the Giants organization as a hitting coach for the Arizona League Giants “Orange” team, one of their two Arizona League teams.