In December 2007, Palacio participated in the 2007 FIFA Club World Cup, playing in Boca Juniors' 1–0 victory over Tunisian club Étoile du Sahel on 12 December. On 16 December, he would score an equalizer to make the score 1–1 against Milan, as the Italian side eventually won 4–2. Palacio earned the Bronze Ball trophy in the tournament, being ranked as the third best player behind Milan players Clarence Seedorf and Kaká respectively. Palacio's performance in the 2008 Copa Libertadores helped Boca avoid elimination from the group stage by scoring twice against Mexico's Atlas in a 3–0 home victory and scoring the third goal in Boca's dramatic 4–3 win against Chile's Colo-Colo. On 7 May 2008, Palacio scored in a 2–1 second-leg win against Brazilian club Cruzeiro. Boca eventually reached the semi-finals, where they would lose to Fluminense.
Despite a minor injury that would see him sidelined for a small portion of the second half of the year, Palacio would then go on to win the Recopa Sudamericana against Arsenal de Sarandí, scoring one goal in the first leg and another goal in the second leg. He later won the Torneo Apertura after the title had to be fought out between the top three team's that were equal on points, Boca, San Lorenzo and Tigre. The championship play-offs were all held at Racing Club's stadium in a round-robin format and were held on 20 December 2008. Palacio would score in a 3–1 win against San Lorenzo to help claim the title.
In July 2009, Palacio signed a contract with Genoa marking the passage in European football. His debut in Serie A falls on August 23, in a 3–2 win over Roma. On November 5, he scores the first goal for the club and in UEFA competitions. In Serie A, the striker unlocks his record against Parma, which - in retour half - takes a double from him. 2 years after his debut, Palacio also enters in Coppa Italia statistics with a new brace. On last appearance for Genoa, the hundredth overall, receives the only red card.
On 22 May 2012, Genoa president Enrico Preziosi confirmed that Palacio would join Inter for the 2012–13 season. On 7 June, he was officially sold to Inter for €10.5 million, signing a three-year contract paying the player €2.7 million per annum.
Palacio debuted in a UEFA Europa League qualification match against Croatian side Hajduk Split. He scored his first Inter double in a friendly against Bizertin of Tunisia on 18 August. He then scored his first official goal for Inter on 23 August in the play-off round of Europa League qualifiers against Romania's Vaslui. He scored again in the return leg in Milan on 30 August, making the final score 1–1 as Inter progressed to the competition's group stage.
He scored his first goal in Serie A for Inter on 21 October in a 2–0 victory at the San Siro against Catania. On 4 November, he scored the final goal in a 1–3 win against defending league champions Juventus while on 8 November, he scored a brace in a Europa League match against Partizan (1–3) that took Inter into the competition's round of 32 with two group stage matches to spare. During a second round match in the Coppa Italia against Hellas Verona on 18 December, after an injury to goalkeeper Luca Castellazzi and after all three of the club's substitutions were exhausted, Palacio, wearing Vid Belec's jersey number 27, was put into goal for the final 15 minutes of the match. He did not concede a goal to the opposition in a 2–0 final win and even made a fine save in the 91st minute, stopping a diving header from the right side of goal by Verona midfielder Alessandro Carrozza.
On 14 February 2013, in a match against Romanian side CFR Cluj in the first leg of the Europa League Round of 16, Palacio was substituted in seven minutes into the game after a season-ending injury to starter Diego Milito. Palacio came on and finished the game with both goals scored in a 2–0 victory. On 3 March, against Catania, Palacio was substituted in at the beginning of the second half at a time when the Nerazzurri were down 2–0. Palacio went on to provide an assist for Ricky Álvarez's goal, then scored twice himself, leading Inter to a 2–3 comeback victory. On 3 April, Palacio scored his second double of the league season against Sampdoria, raising his tally to 12 goals scored; in the same game, however, he strained his left hamstring, ultimately ending his season prematurely.
In the first fixture of the season, Palacio scored a brace against Cittadella in the third round of the Coppa Italia. He also scored in the first league game of the season, against Genoa on 25 August; his goal came in injury time, giving Inter a 2–0 win, which was followed by another goal and an assist in a 3–0 win against Catania. On 20 October, Palacio scored twice to give Inter a 3–3 draw against Torino at the Stadio Olimpico, and six days later scored in a 4–2 triumph against recently promoted Hellas Verona at San Siro. On 3 November, Palacio continued his fine form, scoring a header and assisting in a 0–3 away win against Udinese at the Stadio Friuli. On 22 December, he scored a superb goal in the 86th minute with the back of his heel after an assist from Fredy Guarín, which proved to be decisive with Inter winning 1–0 against Milan. That was his first competitive goal in the Derby della Madonnina. Thanks to his goal, Inter ended 2013 with a win and situated in fifth place with 31 points.
On 15 February 2014, Palacio scored his first goal of 2014 after some negative displays during the 2–1 away win against Fiorentina. On 9 March, he scored the winning goal against Torino at the San Siro, giving Nerazzurri three important points. Five days later, Palacio signed a new two-and-a-half year contract with Inter which will keep him at the club until 2016. One day after he extended his contract, Palacio scored the opening goal and assisting the winner of Jonathan in the 2–0 away win against Hellas Verona. Palacio continued with his good appearances by scoring his 15th league goal in the 4–0 thrashing of Sampdoria at the Stadio Luigi Ferraris. He also assisted both goals from Mauro Icardi.
On 10 May, in Javier Zanetti's last competitive match at the San Siro in which Inter defeated Lazio 4–1 to secure a place in Europa League play-off for next season, Palacio scored a brace and in both occasions went to celebrate with Zanetti. He was first assisted by Mateo Kovačić and later by Yuto Nagatomo. Palacio ended the 2013–14 season with 39 appearances (37 in Serie A) and 19 goals (17 in Serie A), finishing as Inter's top goalscorer.
Palacio missed all of the pre-season phase due to his international duties with Argentina at the 2014 World Cup. He was not called upon for the first official match of the season against Icelandic side Stjarnan in the first leg of the play-off round for the Europa League, after Inter head coach Walter Mazzarri decided to let him rest. He also did not play in the returning leg as Inter comfortably secured qualification for the group stage with an aggregate 9–0 score. After missing the opening match of the Serie A season, Palacio made his first appearance of the season on 14 September, playing the last 14 minutes of the 7–0 thrashing of Sassuolo.
Palacio scored his first goal of Inter's season on 15 December 2015 in a 3–0 thrashing of Cagliari at the San Siro, moving Inter on from the Coppa Italia's round of 16. On 8 January 2016, he extended his contract with Inter for a further season, keeping him at the club until June 2017.
On 29 September, he scored Inter's only goal in the 3–1 defeat against Sparta Praha. With his contract lasting until the end of this season, he played his last game for Inter on 28 May 2017.
On 17 August 2017, Palacio signed a one-year contract with Bologna.
Palacio played his first match with the Argentina national team on 8 March in a friendly match against Mexico which ended in a 1–1 draw at Los Angeles Memorial Coliseum. Later that month, on 25 March, he played his first competitive match, a 2006 FIFA World Cup qualifier, against Bolivia, which ended with a 2–1 away victory, with Palacio playing the last eight minutes of the match. He was selected by the coach José Pékerman for the following year's World Cup, and was given the shirt number 14. He made his debut in the tournament, entering in the field in the 64th minute and helping the team to win the first match of Group C against the Ivory Coast in a 2–1 victory. He did not play any more matches until the end of the tournament, with Argentina finishing the tournament in the quarter-finals after losing 4–2 on penalties against Germany.
Under new Argentina coach Alfio Basile, Palacio was selected for the 2007 Copa América and given the shirt number 7. He played his first match in this tournament in the team's last match in Group C against Paraguay, starting and playing 90 minutes in a 1–0 victory at the Estadio Metropolitano de Fútbol de Lara. Argentina finished as group winners, beating the United States, Colombia and Paraguay. He made his second appearance after playing the last 12 minutes in a 3–0 win against Mexico, securing Argentina's place in the semi-finals of the tournament. In the final, he was an unused substitute as Argentina lost 3–0 to rivals Brazil.
On 15 June 2008, more than three years after his debut with Argentina, Palacio scored his first goal for his country via equalizer in the 93rd minute in a 1–1 draw against Ecuador for the round 5 of 2010 World Cup qualification. He played only two matches in 2008, and did not play any minute for the national team during 2009 and 2010, meaning that he was not included in the squad for the 2010 World Cup by coach Diego Maradona.
After his good form with Genoa during the second part of the 2010–11 season and first part of 2011–12, Palacio received his first call-up by new national team coach Alejandro Sabella for the 2014 World Cup qualifying match against Venzeuela. On 11 October 2011, he played his first match for the national team after a three-year absence, entering the field in the final 15 minutes of a 1–0 loss against Venezuela, with defender Fernando Amorebieta scoring the only goal of the match.
After an impressive 2012–13 season with Inter, Palacio became a regular member of the Argentina national team under Sabella. During the qualifiers for the 2014 World Cup, he played eight matches and helped Argentina finish first place in its group with 32 points. He scored his second goal for Argentina on 11 October 2013, scoring the third goal in the 3–1 victory against Peru in round 17 of the qualifiers. During this year, he was an important player in Argentina's qualifiers, assisting several goals.
Palacio's good form continued even in 2014, scoring the third goal with the national team on 4 June 2014 in a 3–0 win against Trinidad and Tobago. He scored after a corner kick taken by midfielder Ángel Di María. Later in that match, he made a good run by dribbling the goalkeeper and assisted the third goal of the match scored by winger Ezequiel Lavezzi. After playing another friendly match against Slovenia, the team traveled to Brazil to play in the 2014 World Cup; he was included on the list of 23 players selected by coach Alejandro Sabella to participate.
On 8 September 2014, at the age of 32, Palacio retired from international football, saying that there are better players to take his spot on the national team.
Palacio is a tactically intelligent and technically gifted player, with an eye for goal. A versatile forward, he is capable of playing in several offensive positions, and has been deployed as a striker, as a second striker, and as a winger. In addition to his skills, he is also known for his defensive work-rate.As of 28 May 2017
As of 13 July 2014
Primera División (3): 2005 Apertura, 2006 Clausura, 2008 Apertura, Runner-up 2006 Apertura, 2007 Clausura, 2008 Clausura
Copa Libertadores: 2007
Copa Sudamericana: 2005
Recopa Sudamericana (3): 2005, 2006, 2008
FIFA Club World Cup: Runner-up 2007
Copa América: Runner-up 2007
FIFA World Cup: Runner-up 2014
South American Team of the Year: 2005, 2006
Primera División top scorer: 2006 Apertura
FIFA Club World Cup: Bronze Ball 2007