Born in Mansoura, Zaki started his career at El Mansoura. He moved to ENPPI for the 2003–04 season. At ENPPI, he became the Egyptian Premier League top goalscorer for the 2004–05 season and helped the club win its first trophy, the 2005 Egyptian Cup, as well as being runners-up in the Egyptian Premier League, After impressing in the 2006 African Cup of Nations, Zaki caught the attention of many clubs, such as El Zamalek and Al-Ahly from Egypt, Al-Ain FC from the UAE, and Nantes from France. But Zaki later decided to play for Russian club Lokomotiv Moscow, who signed him for a reported sum of €1.7 million. However, he did not play a single match for Lokomotiv.

In 2006, Zaki moved back to the Egyptian Premier League and signed to play for El Zamalek. Owing to his powerful physical displays as a forward, fans nicknamed him the “Bulldozer” and newspapers nicknamed him the “Egyptian Gladiator”.

Zaki played for the Egyptian National Team. In the 2006 African Cup of Nations Zaki scored the winning goal for Egypt in the semi-final against Senegal late in the second half, with his first touch moments after coming off the bench to replace a visibly irate Mido – whose argument with coach Hassan Shehata held up play and resulted in a six-month international ban from the Egyptian Football Association for the player. Egypt later went on to win their fifth continental title.

On 22 July 2008, Wigan Athletic completed a one-year loan deal to bring Zaki to the JJB Stadium for a sum of £1.5 million. After scoring two goals in his two pre-season appearances for Wigan, Zaki scored on his league debut on 16 August against West Ham United. On 30 August he scored his first brace for Wigan in a 5–0 victory over Premier League new-boys Hull City. On 13 September he scored his fourth goal in as many games in the Premier League as Wigan drew with Sunderland, putting him joint top of the goal scoring charts alongside Jermain Defoe. On 28 September, Zaki scored again in the Premier League from the penalty spot against Manchester City, and this goal took him to the top of the goal scorers list with 5 goals in 6 games. He followed it with two more goals against Liverpool, further solidifying his position as top scorer in the English Premier League. He also scored penalties in 2–1 victories over Portsmouth and Newcastle. At one point he was the third top scorer in the Premier League behind Chelsea’s Nicolas Anelka and Manchester City’s Robinho who had 15 and 12 respectively to Zaki’s 10, however he failed to add to that tally in which Anelka finished top with 19.

Two years later in the 2008 Africa Cup of Nations, Zaki scored a goal against Zambia in the group stage and another in the quarter final against Angola. Additionally, he scored another header and then added another goal in the semi-final match against Ivory Coast. Egypt again went on to win the title for a record sixth time. He was chosen in the CAN 2008 All Star Starting XI.

In April 2009, Zaki failed to return to Wigan Athletic from one of Egypt’s World Cup qualification matches, leading his former-club manager, Steve Bruce, to label him as the most unprofessional player he had ever worked with. His late returns from international duty led to Bruce publicly branding Zaki “highly unprofessional” and fining him the maximum amount permitted, which he has done on more than one occasion; “Before this latest incident, Zaki had already been fined considerably more than the average person in Britain earns in a year and he will now face another heavy fine”. However, Bruce said that repeatedly fining him does not seem to alter his poor behaviour. Bruce subsequently confirmed on 17 May 2009 that the club will not be taking up the option of making his loan deal permanent.

On 17 January 2010, Zaki passed a medical with Hull City moving to the club on a 5-month loan. On 30 January 2010 he made his debut for Hull coming on as substitute for Jozy Altidore in the 69-minute. Hull went on to draw the match 2–2 with Wolverhampton Wanderers. Amr Zaki quoted “If an offer from a decent club does not come up by the end of my time at Hull, then I will return to Zamalek.” On 17 April 2010 it was confirmed by his agent that his loan had been terminated and he returned to Zamalek.

Zaki returned to Zamalek at the beginning of the 2010–11 season and gave phenomenal performances becoming the team’s top scorer after scoring 3 goals in the league’s first 4 matches. However, in October 2010 Zaki suffered a career threatening injury that kept him away for the better part of 10 months. Zaki returned from injury and participated with Zamalek in the Egypt Cup, scoring twice in the semi-final match against defending champions Haras El-Hodood, thus leading his team to qualify for the final with a 2–1 victory.

In November 2011, Zaki had a financial dispute with Zamalek board over his unpaid wages, claiming that he hasn’t been paid over a year. The dispute lasted 3 months before Zamalek chairman, Mamdouh Abbas, paid Zaki a large percentage of his late wages. Zaki made his first appearance for Zamalek after the dispute, coming on as a second-half substitute in a Round of 64 CAF Champions League game against Tanzanian club Young Africans. Zaki scored the equalizer goal in the 74th minute, and the game finished 1–1.

On 5 June 2012, Zaki told Egyptian sports website FilGoal that he relished a return to play in England again. This came in parallel with Egypt U-23 coach Hany Ramzy statement that Zaki may be called up to play for Egypt in the 2012 London Olympics U-23 tournament as one of the 3 allowed overage players. Zaki commented on that by saying, “I think it’s a good chance for me to re-appear on English grounds. It is an opportunity to be watched again.” Eventually, Zaki was not picked for the Olympics by Ramzy. However, since Zamalek continued to face financial problems throughout 2011 and 2012, Zaki started to be considered on his way out of the club as a way to bring in cash. Gaziantepspor and other Turkish sides along with some English teams and other Persian Gulf sides have all shown their interest in Zaki. On 20 July 2012, English Championship side Blackpool sent an official request to the player to go on a one-week trial at the club. Zaki and Zamalek had accepted the trial offer, but Blackpool later pulled out of the transfer negotiations and cancelled their trial offer. Fellow Championship club Middlesbrough had also shown an interest as well. Zaki stated his desire to join Middlesbrough after speaking with his former teammate Mido about the club and insisted on a two-year contract, but Manager Tony Mowbray only offered Zaki a deal until the end of the season. Zaki turned down the offer. Zaki’s agent later said, Everything was agreed, his medical, his contract, his house, but Middlesbrough changed their minds at the last minute. Amr wanted to join Middlesbrough and help them win promotion, it was not about money. Amr was ready to travel. A Middlesbrough spokesman stated that Zaki was one of a number of players being chased by the club, and no offer was submitted to the player.

In late July 2012, Turkish side Gaziantepspor offered Zamalek club 250,000 Euros for Zaki, and Zamalek accepted the offer on 31 July 2012. However, speculation appeared on the bid after Gaziantepspor failed to send the official contract on the agreed deadline. Because of that, Zaki’s move to Gaziantepspor was thrown into doubt, and fellow Turkish side Elazığspor began to show interest in signing the player. On 6 August, Elazığspor club official Selçuk Cengiz Öztürk stated that Elazığspor have reached an agreement with Zamalek to sign Zaki according to Elazığspor manager Bülent Uygun and it is expected that he will join on a three-year deal. He later stated that he will arrive in Egypt on Monday 7 August to complete the move. On the next day, Gaziantepspor officially dropped out of the negotiations with Zamalek due to unstated reasons. Later on, Elazığspor officially signed Zaki on a two-year deal, for the same price which Gaziantepspor had previously offered (250,000 Euros) During the contract agreement phase, Zaki requested to put a special clause in his contract which states that if Elazığspor get relegated to the Turkish second division, Zaki would be free to leave the club if he wants.

After Egypt’s failure to qualify to the 2010 FIFA World Cup, Zaki was fairly absent from the national squad for almost two years due to his many injuries with Hull City and Zamalek for the 2009–10 and 2010–11 seasons. After American Bob Bradley took over as coach of the national team, Zaki had been called up to the squad three times (November 2011, March 2012, and April 2012) and Zaki dropped out of the squad due to injury each time. Bradley was “done with Zaki” after citing an ear infection being the reason for Zaki to drop out for the third time. Media reported that Zaki was trying to avoid the national team and playing under Bradley, but he denied these rumors claiming that he ready to be called up at any time from now on. And finally after a lengthy absence from the national team, he was recalled by Bradley in October 2012 to play two friendlies against DR Congo and Tunisia. After nearly a 4-year goal drought, Zaki scored in the 2014 FIFA World Cup qualifier against Guinea on 10 September 2013, scoring the fourth goal in the 4-2 win.

After being close to signing with Ukrainian giants Shakhtar Donetsk in the 2013 winter transfer window, Zaki made a surprise move to former club ENPPI that surprised Egyptian and football fans around the world. Zaki had signed for 2 and half years keeping him at the Egyptian club until June 2015. It was mostly expected that Zaki would return to his home club Zamalek once again but Zaki had explained that the Zamalek chairman Mamdouh Abbas had “rejected his return to Zamalek.” Twelve days after his signing with the club, Zaki and the club had terminated the player’s contract after a “disagreement” between the two sides. And Zaki was once again a free agent.

On 18 June 2013, Zaki officially signed for Kuwaiti club Al-Salmiya for one year and was presented to the press a few days after. He received the number 9 jersey. On his debut, Zaki scored in the league opener against Yarmouk scoring the final goal in Al-Salmiya’s 4-0 win. In the third game of the season against Kazma, he scored his 2nd goal in 3 games scoring Al-Salmiya’s first goal in a 3–1 win over the Kuwaiti giants. After suffering a couple injuries and some minor issues with his salary, in December 2013 Zaki and Al Salmiya agreed to terminate the player’s contract to prevent any more financial issues and also because Zaki wasn’t performing as well as he’d hoped in the Kuwaiti Premier League and wanted to move to Europe or a different Arab League. Zaki ended his stint with Al Salmiya with 2 goals and an assist from 9 matches.

On 30 December 2013, it was reported that Zaki was going to join Moroccan champions Raja Casablanca on 1 January 2014 when the winter transfer window re-opened. In a friendly match, Zaki broke his foot and ankle ligaments and required surgery which would leave Zaki out action for up to 3–4 months, which resulted in him missing the rest of the 2013–14 season. However, controversy broke out when the club claimed they had no knowledge that Zaki went to do a surgery on his foot, and they later expressed their anger with Zaki for not letting the club officials know that he was going to perform a surgery. Raja Casablanca and Zaki later agreed to the termination of the contract to avoid any further issues. Zaki featured in three friendlies during the club’s winter break, scoring 1 goal. He never made an official competitive appearance for Raja Casablanca. And for the fourth time in two years, Zaki was once again a free agent.

On 16 August 2014, Zaki signed a one-year deal with Lebanese Premier League club Al Ahed. The transfer was the most expensive in the history of the league to date. On 12 September 2014, he terminated his contract with the club due to injury concerns. He didn’t play a single game with the club.

In January 2015 he signed with El Mokawloon an 18-month-contract uniting with his former coach in national team Hassan Shehata. He made his return to football after almost 400 days away from the game in round 32 in Egypt Cup.

On 18 August 2015, Zaki announced retirement from football via his Twitter account.