He faced a series of injuries and heavy competition from teammates Giovane Élber, Roy Makaay and Claudio Pizarro which limited his impact and restricted his appearances for the club.

[10] During the group stages of the 1998 Copa Mercosur, Santa Cruz scored his first goal of the competition in the 11th minute of Olimpia Asunción's 4–2 away victory against Argentine side Racing Club on 14 October 1998.

In Olimpia first group stage match, against Cerro Porteño on 24 February, Santa Cruz scored a second-half double past Aldo Bobadilla in the 58th and 89th minutes as his side were defeated 4–3.

[17] In Olimpia's fourth group stage fixture, Santa Cruz featured in the entire match as his side drew 2–2 at home against Cerro Porteño on 17 March.

[18] On 26 March, Santa Cruz played a full 90 minutes in Olimpia's 2–1 home defeat against Corinthians in their fifth Copa Libertadores group stage fixture.

[14] Santa Cruz had scored two goals in five Copa Libertadores appearances and would not take part in his club's last group stage fixture, a 4–0 away defeat against Corinthians on 9 April, due to his participation for Paraguay U20 at the 1999 FIFA World Youth Championship, which was disputed at the same time.

[37] He missed a large amount of the Champions League, he made his return where he was brought onto the field for Giovane Élber on 65 minutes in the second-leg quarter-final 2–1 win against Manchester United on 18 April.

[52] Giovane Élber transferred to Lyon, but Bayern Munich signed Dutch striker Roy Makaay which provided more competition between Santa Cruz and Claudio Pizarro for the 2003–04 Bundesliga season.

[57] He featured in the following two matches, although due to an injury sustained, he made his fourth and final league appearance for the 2004–05 season on matchday 34 in a 3–1 away win against VfB Stuttgart on 21 May 2005; he was substituted onto the field for Bastian Schweinsteiger in the 77th minute.

[70] Santa Cruz made his first appearance in the 2006–07 Champions League in a 4–0 home win against Spartak Moscow on 12 September, where he scored Bayern's second goal with a right-footed shot in the 52nd minute.

After eight years with Bayern, he stated to the club's director of football, Uli Hoeneß, that he needed a change of scenery and opted for a transfer to Real Betis, he also received offers to go to Italy and England.

[94] Prior to the start of the 2008–09 season, Blackburn signed Roque's younger brother, Julio, who had arrived from Paraguayan Primera División side Cerro Porteño.

[97][98] During an away fixture against Portsmouth in December 2008, Santa Cruz's front door was forced open and his house was raided by three men who held his wife, Giselle, at knifepoint to her throat.

On 21 June 2009, it was reported that Santa Cruz was undergoing a medical at Manchester City ahead of a proposed summer transfer worth £17.5 million on a four-year deal.

Santa Cruz debuted for Manchester City in the 2009–10 Premier League season in a 3–1 home victory against West Ham United on 28 September, where he was substituted onto the field for Shaun Wright-Phillips in the 81st minute.

[128] In December, Brazilian Série A outfit Cruzeiro had made a bid for Santa Cruz and had also offered Manchester City their highly rated 17-year-old youngster, Léo Bonatini, as part of the deal.

Santa Cruz made his 2014–15 La Liga season debut in a 1–0 home victory against Athletic Bilbao on 23 August, playing in the entire 90 minutes of the fixture.

[180] Concluding the fixture, Málaga club president Abdullah bin Nasser Al Thani used his Twitter account in order to say goodbye to the Paraguayan striker, saying, "Thank you very much Roque Santa Cruz.

[190] One week after his debut, Santa Cruz was substituted off of the field after just 14 minutes of the first half in a 1–0 home victory against Santos Laguna on 17 January with reports that he had suffered muscle pain in the outer thigh.

[211] Santa Cruz was labelled 'Roque-Mania' by newspaper Versus, who described the 2018 and 2019 seasons as when his return to Olimpia Asunción reached its top, following four consecutive domestic titles under the coaching of Daniel Garnero.

[221] On 7 May 2024, aged 42 years, 8 months and 21 days, during an away game against Deportivo Táchira, he scored the equalizer to rescue his team a point and become the second-oldest Copa Libertadores goalscorer.

Since he already debuted in Paraguay's domestic league, national team coach Paulo César Carpegiani contemplated taking a then 16-year-old Santa Cruz to the 1998 FIFA World Cup in France.

[236] On 15 June 2008, Santa Cruz scored Paraguay's first goal in their 2–0 home victory against Brazil in Asunción, hitting a far-post tap-in, side footing the ball into the net after receiving it from a corner.

[239] Santa Cruz went on to score two more goals (against Bolivia and Argentina) during the 2014 World Cup qualifiers, and also served as the national team captain for the last four fixtures of the campaign.

He scored in the 39th minute, giving Paraguay a 1–0 first half lead, when he latched onto the end of a free-kick by Francisco Arce and headed the ball into the left side of the net.

[253] On 10 June 2013, it was reported that José Luís Chilavert had stated that Santa Cruz had pretended to be injured in order to miss the match against Germany at the round of 16 stage of the 2002 World Cup.

[264] Santa Cruz scored three times during qualification for the 2010 World Cup, including the opening goal of a 2–0 defeat of Brazil in Asunción,[265] as La Albirroja finished third in the CONMEBOL standings.

Paraguay had beat Venezuela 5–3 via penalty shoot-out and qualified for the final where they faced Uruguay at the Estadio Monumental Antonio Vespucio Liberti in Buenos Aires on 24 July.

[citation needed] On 7 June 2013, in a 2014 World Cup qualification match against Chile, Santa Cruz scored his 26th international goal and became the leading goalscorer for Paraguay.

Santa Cruz was described in his 2010 World Cup profile as having "long caused problems for opposing defences with his natural flair for goalscoring and surging runs into the penalty box".