In August 2007, Higuaín signed a three-year contract at Beşiktaş J.K. of the Turkish Süper Lig, for a US$1.65 million fee. He did not settle in Istanbul, and the following February he was loaned to Mexico’s Club América.

Higuaín signed for the Columbus Crew as the team’s third ever designated player on 27 July 2012, for a then club record fee of $650,000 USD. He made his debut on 19 August as a substitute against the Houston Dynamo and assisted on the go-ahead goal by Eddie Gaven with a ball over the top 13 minutes later. Three days later he got his first MLS start against Toronto FC, and in the fourth minute again set up a Gaven opener, then scored the winning goal himself. In the next game on 26 August, he scored two goals from free kicks in an eventual 4–3 victory over the New England Revolution. For his performances over his first several matches, Higuaín was named the Major League Soccer Player of the Week for weeks 25 and 26, of the 2012 Major League Soccer season by North American soccer journalists. He finished the season by scoring both goals of a 2–1 victory against Toronto FC on the final matchday.

Following the 2014 Major League Soccer season in which Higuaín tallied a team-leading eleven goals and seven assists, he was signed to a new contract, the most lucrative deal ever given by the Crew. It was reportedly a two-year contract although terms of the deal were officially undisclosed. At the time of signing his new contract, Higuaín had been ranked fifth in the league in goals, first in penalty kick goals, and one of only eight players to score double-digit goals in the previous two seasons since entering the league.

In 2015, Higuaín scored eight goals and provided nine assists during the MLS regular season, while in the playoffs, he won the Eastern Conference Championship with Crew, only to miss out on the MLS Cup Final to Portland, following a 2–1 home defeat. The following season, Higuaín had a disappointing season, scoring only four goals and adding three assists in just 20 appearances, as Crew missed out on the playoffs. While many pundits expected him to leave the next season, as his contract was expiring, he signed a one-year extension, and in 2017, he helped Crew to qualify for the playoffs and reach the Eastern Conference finals.

On 25 May 2019, in a game against the Colorado Rapids, Higuaín was injured, and subsequently received anterior cruciate ligament surgery, ruling him out for the remainder of the season. On 21 October 2019, Columbus Crew’s president and general manager, Tim Bezbatchenko, announced that the club decided not to extend his contract for the next season.

On 2 March 2020, Higuaín joined D.C. United as a player and Player Development Coach. On 13 July 2020, he made his first appearance in an “MLS is Back” tournament match against Toronto FC. With D.C. United losing 2–0 and at a man disadvantage due to a first-half ejection, Higuain came on as a substitute in the 80th minute and scored on a breakaway in the 84th minute. D.C. United added a second goal in injury time to force a 2–2 draw.

On 10 October 2020, D.C. United traded Higuaín to Inter Miami in exchange for $50,000 in General Allocation Money, where Higuaín joined his brother, Gonzalo Higuaín.