January 2001, he made his professional debut for Triestina in 2000–01 Serie C2 (the fourth division), subsequently returning to Treviso in June 2001, via Milan.

Borriello left Sampdoria in January 2006 for a six-month loan stint at Treviso where he scored his then-career best of five Serie A goals.

Borriello was recalled to Milan's first team in the summer of 2006 after Andriy Shevchenko was sold to Chelsea and Marcio Amoroso terminated his contract.

Moreover, his career was briefly put in jeopardy when on 21 December 2006 it was revealed that he tested positive for prednisolone and prednisone after the 11th game of the 2006–07 Serie A season against AS Roma played on 11 November 2006.

[8] As a result of his suspension, he was also excluded from the club's Champions League squad list and, therefore, was not able to participate in any playoff games leading up to Milan's victory over Liverpool in the final.

Incidentally, in the return fixture on 24 February 2008 in Udine, Borriello hit another hat-trick in a 5–3 away win, reaching 15 league goals in the process.

He finished the season with 19, making him the third-highest goalscorer in the league behind Juventus pair Alessandro Del Piero and David Trezeguet.

After Kaká left the club in the summer 2009 transfer window, Borriello chose to switch to shirt number 22, which he had worn at Genoa.

Borriello scored another brace in Milan's 5–2 defeat of former club Genoa, one of his goals being an acrobatic bicycle kick from a cross from Ronaldinho.

The following week, Borriello scored a lovely goal against Siena when he hooked a 30-yard chipped pass from Andrea Pirlo into the top corner of the net.

On 31 August 2010, he was loaned to Roma for free (where he then scored the winning goal against Milan at the San Siro on 19 December),[14] with the obligation to purchase the player's rights before the 2011–12 season for a total of €10 million split over three years (a general practice in Italy), as a direct consequence of the arrival of forwards Zlatan Ibrahimović and Robinho.

[25] On 31 August 2012, the final day of the Italian transfer market, Genoa signed him from Roma and sent Alberto Gilardino to Bologna, also in temporary deal.

[27] After making eight appearances and scoring three times, Borriello then suffered a trauma injury in the right ankle, putting him out of action for 45 days.

[30][31] He made only two substitute appearances for West Ham before a calf-strain injury in February marked the end of his playing time for the London-based club.

[32][33] After not making any appearances for Roma in the 2014–15 season, Borriello sealed a permanent return to Genoa for the third time on the final day of the January 2015 transfer window.

[39] On 30 January 2019 he announced his retirement through his Instagram profile, after having consensually terminated his contract with the club, concluding his spell on the Balearic Island with only 7 appearances and no goals to his name.

[49][50][51] A hard-working player, while he is mainly known for operating in the penalty area, he has also drawn praise for his defensive contribution off the ball and willingness to track back.

[55] Off the pitch, Borriello has often attracted attention in the media due to his high-profile relationships;[45][56] from August 2004 to December 2008, he dated Argentine–Italian showgirl Belén Rodríguez.