Prior to the 2001 season, Hamilton was involved in an automobile accident. His mother and father were also injured but recovered. The 2001 season marked the beginning of Hamilton’s drug and alcohol use, and he made his first attempt at rehabilitation. Hamilton only played 45 games in the 2001 season, split between the Charleston (Single-A) and the Orlando Rays, a Double-A team in the Southern League. Hamilton began the 2002 season with the Bakersfield Blaze, batting .303 with nine home runs and 44 RBIs in 56 games before his season came to an end due to lingering toe and neck injuries. The Devil Rays noticed a change in Hamilton and reacted by sending him to the Betty Ford Center for drug rehabilitation.

Hamilton was married to Katie (née Chadwick), the daughter of Michael Chadwick who helped guide him in his recovery from drugs and alcohol abuse for several years. They started dating in 2002 when he returned to Raleigh, and married in 2004. In early 2015, shortly after another substance-abuse relapse, Hamilton filed for divorce from Katie after 11 years of marriage. The couple had three daughters together, along with Katie’s daughter from a previous relationship.

On May 8, in a 10–3 win over the Baltimore Orioles at Camden Yards, Hamilton registered multiple career-highs; he had five hits in five at-bats, hitting four two-run home runs and a double for a total of eight runs batted in. Incidentally, the only runner on base each time was Elvis Andrus. In doing this, he not only became just the 16th player in MLB history to hit four home runs in one game and the first to do so since Carlos Delgado in 2003, but also now holds the American League record for most total bases in a single game with 18. Hamilton was one base shy of tying the Major League record.

During spring training of the 2003 season, Hamilton failed his first drug test. At the start of the season, Hamilton showed up late several times during spring training and was reassigned to the team’s minor league camp. He left the team and resurfaced several times, but eventually took the rest of the season off for personal reasons. Hamilton was hoping to return to spring training with the Devil Rays in 2004, but he was suspended 30 days and fined for violating the drug policy put in place by MLB. A “failed” test is one in which there is a positive result for a drug more severe than marijuana. A month later, MLB suspended him for the entire season after he failed two more tests.

During the days of his most prolific abuse, Hamilton met a businessman named Michael Chadwick, who made an attempt to steer him in the right direction. It was through this relationship that he ended up meeting his wife, Katie, who was Chadwick’s daughter. Hamilton’s return to baseball was helped along by former minor league outfielder and manager Roy Silver, who owned a baseball academy in Florida. After hearing about Hamilton’s desire to return to baseball, Silver offered the use of his facility if Hamilton agreed to work there. Hamilton first started working at Silver’s Academy in January 2006. His duties included cleaning the bathrooms and raking the infield. Hamilton spent his nights sleeping on an air mattress in one of the facility’s offices. After several months there, Hamilton attempted to play with an independent minor league team, but MLB stepped in and disallowed it.

Hamilton was allowed to work out with the Devil Rays’ minor league players starting on June 2, 2006. By the end of the month, he was allowed to participate in minor league games. In order for this to happen, the Rays had to run Hamilton through waivers, making him available for any team for $20,000. No team put a claim in for him. Hamilton played in 15 games with the Hudson Valley Renegades at the end of the 2006 season, his second stint with the minor league ball club.

Left off the Rays’ 40-man roster, Hamilton was selected third overall in the 2006 Rule 5 draft by the Chicago Cubs, who immediately traded him to the Reds for $100,000 ($50,000 for his rights, and $50,000 to cover the cost of the Rule 5 selection). In their coverage of the draft, Chris Kline and John Manuel of Baseball America called Hamilton “the biggest name in the Rule 5 in many years”.

Hamilton was one of the Reds’ best hitters in spring training in 2007, leaving camp with a .403 batting average. In order to retain the rights to Hamilton, though, the Reds would have to keep him on their Major League 25-man roster for the entire 2007 season, so they planned to use him as a fourth outfielder.

Hamilton ended up starting most of the season in center field after an injury to Ryan Freel, but he was shut out in the voting for the Rookie of the Year, which was won by Ryan Braun. On December 21, 2007, the Reds traded Hamilton to the Texas Rangers for Edinson Vólquez and Danny Herrera.

Fans selected Hamilton as one of the starting outfielders for the AL at the 2008 Major League Baseball All-Star Game at Yankee Stadium. He finished first in voting among outfielders. He was one of seven first-time starters in the game. Along with Kosuke Fukudome, Geovany Soto, and Ryan Braun, Hamilton was one of four who had made their MLB debut in 2007 or 2008. He was selected to participate in the 2008 Major League Baseball Home Run Derby the evening before the game. Hamilton selected 71-year-old Clay Council to throw to him during the Derby. Council was a volunteer who threw batting practice for him as a child in Raleigh, North Carolina. In the first round of the event Hamilton hit 28 home runs, breaking the single-round record of 24 set by Bobby Abreu in 2005. Hamilton ended up hitting the most total home runs in the contest with 35, but lost in the final round to Justin Morneau, as the scores were reset. His record-setting first round included 13 straight home runs at one point, and seven that went further than 500 feet (150 m). His longest home run was 518 feet. In 2006, when Hamilton was trying to get back into baseball, he had a dream in which he participated in a Home Run Derby at Yankee Stadium, but he could not remember how many home runs he had hit. After the Derby, Hamilton said: “This was like living the dream out, because like I’ve said, I didn’t know the ending to that dream.”

In 2008, Hamilton locked up the Rangers’ starting center fielder job with a stellar spring training. His spring training performance continued into the regular season. Hamilton, usually slotted fourth in the Texas batting order, led all major league players in RBIs for the month of April. He was named AL Player of the Month after hitting .330 with 32 RBIs during the month. Hamilton then went on to win player of the month for the second straight month in May, becoming the first AL player in baseball history to be awarded Player of the Month for the first two months of the season. Hamilton was featured on the cover of the June 2, 2008, issue of Sports Illustrated, in a story chronicling his comeback. On July 9, Hamilton hit the first walk-off home run of his career, against Francisco Rodríguez.

Hamilton’s struggles with drugs and alcohol are well-documented. He finally got clean after being confronted by his grandmother, Mary Holt. In May 2008, Hamilton said he had not used drugs or alcohol since October 6, 2005.

In late 2008 Hamilton, among other celebrities such as Brian Welch and Greg Ellis, appeared in testimonial videos called “I Am Second”, in which he shares his story of recovering from drug use with the help of his Christian faith.

Hamilton spent a portion of 2009 on the disabled list, with a bruised rib cage and an abdominal strain. After visiting doctors in Philadelphia on June 8, 2009, they found a slight abdominal tear, and he underwent a successful surgical operation to repair it the next day. He was expected to be out 4–6 weeks.

Though injured, he was selected by fan voting to play in the 2009 All-Star game, where he was joined by teammates Michael Young and Nelson Cruz. Hamilton finished batting .268 with 10 home runs and 54 RBIs in 2009.

Hamilton confirmed he suffered a relapse in early 2009 after photos were released in August 2009. Sports website Deadspin posted photos of Hamilton shirtless in a bar in Tempe, Arizona with several women. According to reports, witnesses saw Hamilton drinking, heard him asking where he could obtain cocaine, and heard him reveal his plans to go to a strip club later that evening. The photos do not show Hamilton drinking or taking any illegal drugs.

In 2010, Hamilton was moved to left field to put young outfielder Julio Borbon in center field. As in his prior two seasons with the Rangers, Hamilton was again selected to start in the 2010 All-Star Game, as one of six members of the Rangers to represent the franchise at the All-Star Game. Hamilton entered the All-Star Break with a .346 batting average, tied for first in the AL with Miguel Cabrera.

Hamilton hit for a league-leading .359 average in 2010, winning his first batting title. This was the fourth-highest batting average since the end of the 2004 season. He also finished fourth in Major League Baseball in OBP (.411), first in slugging percentage (.633) and OPS (1.044), and tied for 10th in home runs (32), despite missing 29 games due to an injury. Hamilton was also one of 25 players to have 100 RBIs. His performance in 2010 made him a front-runner for the AL MVP Award. Hamilton won the AL Players Choice Award for Outstanding Player in 2010.

On October 22, Hamilton and the Rangers won the 2010 ALCS. It was the first time in Rangers’ history they had gone to a World Series. With four home runs, seven RBIs, and the recipient of several intentional walks in the ALCS win against the Yankees, he won the ALCS MVP Award. On November 23, 2010, Hamilton was voted the AL MVP.

Hamilton avoided arbitration by signing a contract for two years and $24 million on February 10, 2011, with the Texas Rangers. On April 12, in Detroit, he suffered a fracture to his right humerus on a play at home plate. On May 18, Hamilton began a rehab assignment with the Double-A Frisco RoughRiders. He returned to the Rangers’ lineup on May 23, and went 2–4 against Chicago White Sox pitcher John Danks, hitting his first home run of the season on the second pitch he saw during his first at-bat. He was an All-Star in 2011.

In 2011, Hamilton batted .298 with 25 home runs. He was third in the American League in sacrifice flies (10), sixth in intentional walks (13), and eighth in slugging percentage (.536).

Hamilton was selected to appear in his fifth All-Star Game after accumulating the most fan votes by any player in the history of the All-Star Game selection process. José Bautista held the previous record with 7,454,753 votes in 2011 until Hamilton received 11,073,744 in 2012. The record stood until 2015, when Josh Donaldson received 14,090,188 votes.

On December 13, 2012, Hamilton agreed in principle to a five-year contract, worth $125 million with the Los Angeles Angels of Anaheim. This deal became official on December 15.

On February 2, 2012, it was reported that Hamilton had suffered a second relapse with alcohol. He claims to have had two or three drinks before inviting his friend and then-teammate, Ian Kinsler, to talk at the bar. Hamilton held a press conference on February 3, 2012, to apologize for his actions.

During 2014, Hamilton batted .263 with 10 HR and 44 RBIs. In the ALDS against Kansas City, Hamilton went hitless (going 0–13 overall). At least twice during Game 1 of the ALDS there was a runner on second and Hamilton either struck out or grounded out.

During February 2015, Hamilton underwent shoulder surgery to repair the AC joint. While he was recovering, it was revealed that he had a relapse into his drug addiction, which he voluntarily reported to MLB. An outside arbitrator ruled that Hamilton’s voluntary admission did not violate baseball’s drug policy, and he could not be suspended. Despite the ruling, team owner Arte Moreno made comments to the media, implying that he did not want Hamilton back on the team. Furthermore, all Hamilton-related merchandise were removed and recalled from all stores as well as an exchange program being set up. The Players Association and several Angels players spoke up in Hamilton’s defense. The Angels began to lay out a rehab plan for him, but shortly afterwards, reports surfaced that the Angels were looking to trade Hamilton.

Hamilton was traded back to the Rangers on April 27, 2015, for cash or a player to be named later. After a short rehab stint to rehabilitate his injured shoulder between the Rangers AA and AAA Minor League affiliates, Hamilton was called up to the MLB team on May 24, and was inserted to the starting lineup on May 25, in a Memorial Day matchup in Cleveland against the Indians. He recorded his first hit back with the Rangers on May 27. Hamilton had a huge series against the Boston Red Sox from May 28–31, 2015. On May 28 of the same year, Hamilton returned to Texas for the first time in a Rangers uniform since leaving the team after the 2012 season. He received a standing ovation from the crowd and proceeded to hit a double on the first pitch he saw. Hamilton went 2–4 in the game, driving in the only run for his own team in a 5–1 loss. On May 29, Hamilton hit two home runs in his first multi-homer game with the Rangers since 2012, leading the team to a 7–4 victory. Two days later, he hit a pinch-hit two RBI double vs. the Red Sox to win the game in walk-off fashion, 4–3. On July 30, 2015, Hamilton recorded four RBI, a home run and walk off base hit in a 7–6 Rangers’ win over the New York Yankees.

In February 2015, Hamilton relapsed, using both cocaine and alcohol.

Hamilton began the 2016 season on the 15-day disabled list. On May 25, 2016, it was announced that Hamilton would not participate for the entire 2016 season after undergoing knee surgery for the third time in nine months. The Rangers activated Hamilton from the disabled list and released him on August 23, as releasing Hamilton before September 1 would allow them to play Hamilton in the major leagues before May 15, 2017, if they chose to re-sign him.

Hamilton was arrested on October 30, 2019, and charged with injury to a child, a third-degree felony, after being accused of physically assaulting his oldest daughter. On April 8, 2020, Hamilton was indicted on a felony charge for beating his daughter. If convicted, he could face up to 10 years in prison.