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Nsereko was born in Kampala and started his career at 1860 Munich.  He was signed by Brescia in the summer of 2005, aged 16, the minimum age limit allowed by FIFA for international transfer among European Union nations. 

He made his first team debut during 2005–06 Serie B season against Crotone, the last match of the season.  He made 23 appearances for Brescia in all competitions, scoring three goals, before signing for West Ham.[3]

On 26 January 2009, Nsereko signed for West Ham United for an undisclosed fee, thought to have been in the region of £9 million dependent on appearances and other factors,[4][5] on a four and a half year contract.[6] He was given the number 10 shirt, following the departure of Craig Bellamy to Manchester City, which bore the name "Savio".[7] His English football, Premier League and West Ham debut came on 28 January 2009 in West Ham's 2–0 home win against Hull City.[8] He played an important part in West Ham's win against Manchester City on 1 March 2009 by providing the assist for Jack Collison's 71st minute goal.[9]

He failed to settle at West Ham, making just one start and failing to score in any of his ten appearances.  He was sold to Fiorentina for €2.7 million cash, with Manuel da Costa going the other way as part of the deal for free.[10][11] West Ham retain the rights to 50 percent of the player's sell-on fee.[12]

Despite his talent, Nsereko never broke into the first team and in January 2010 was loaned out to Bologna, in what proved to be another disappointing experience, with only two appearances with the Rossoblu.  On July 2010, he was sent back to Germany, joining 2.  Bundesliga side TSV 1860 München on a season loan; the loan agreement was however cancelled unilaterally on 23 October 2010, after the player was reported missing for a week before being found at his sister's place.[13][14][15] In January 2011, Nsereko joined Bulgarian A PFG side Chernomorets Burgas on loan until the end of the season.[16] After this loan spell, he was loaned again this time to Serie B side Juve Stabia.[17] After only one game with the club, Savio was reported missing once again in September 2011, leading his club to ask for unilateral rescission of the contract.  He was successively reported being in London,[18] and, after returning to Italy with a medical certificate only two weeks later, he was allowed to leave to Germany to deal with unspecified personal problems.[19] In January 2012, Nsereko joined Romanian Liga I side FC Vaslui on loan until 31 December 2012.[20][21][22] In July 2012, it was reported in Germany that Nsereko joined 3.  Liga side SpVgg Unterhaching on loan for a season.[23]

After months of speculation, Nsereko finally moved SpVgg Unterhaching of the third division in Germany on 3 September 2012 for free.  In an interview on the club's website, Nsereko cited his desire to play in his home town of Munich as one of the motivating factors for his move.[24] He was released by Unterhaching after 2 months with the club.[25] Fiorentina also stated in its financial report ending on 31 December 2012, that Savio was released due to breach of contract on Savio's side.  Fiorentina had rights to claim damages for Savio's residual contract which ending on 30 June 2016.  It was reported that Savio faked his own kidnapping in Thailand.[26]

In October 2012, Nsereko was arrested by the police in the Thai resort of Pattaya on a false kidnap claim.  He had reportedly attempted to extort €25,000 from his family by telling them he had been kidnapped and demanding a ransom.[37]