Born in Kabwe Central Province, Zambia, Mayuka began his career at the Lusaka Academy at the age of 11. In 2007, he joined Kabwe Warriors, one of the biggest clubs in Zambia owned by the national railway company Zambia Railways. In this team, he flourished scoring 15 goals in 23 games. He consequently was selected to the Zambia under-17 national team.

Mayuka debuted for the senior side in the 2007 COSAFA Cup, scoring the second goal in a 3–0 defeat of Mozambique. Mayuka scored the first goal for Zambia of 2012 Africa Cup of Nations which was score again by his teammate Rainford Kalaba second goal in the game with Zambia earning a victory against Senegal. In the same tournament, he scored against Libya in the group stage, and then he scored the winner in a famous 1–0 victory over Ghana in the semifinals, therefore leading Zambia into the finals. He then played all 120 minutes against Ivory Coast in Zambia’s penalty shootout victory against Ivory Coast.

In September, he joined Israel’s Maccabi Tel Aviv. Before opting to join Maccabi Tel Aviv, Mayuka was close to signing for Portuguese side Porto, but the move never materialised. When he moved to Maccabi Tel Aviv, Mayuka joined the youth team where he scored three goals. In April 2010, Mayuka renewed his contract at Maccabi Tel Aviv until 2014.

On 28 May 2010, it was confirmed that Mayuka had signed a five-year contract with Swiss club BSC Young Boys for a transfer fee of £1.7m as a replacement for Seydou Doumbia, who was sold to CSKA Moscow. On 1 December 2010, Mayuka scored two goals in the Europa League against Stuttgart in a 4–2 win. On 17 February 2011, Mayuka scored a last-minute goal against Russian club FC Zenit Saint Petersburg in UEFA Europa League match to help his team to a 2–1 home win.

On 28 August 2012, he joined Premier League side Southampton on a five-year deal for an undisclosed fee, reported to be £3 million. He made his debut for Southampton against Manchester United at St. Mary’s Stadium on 2 September 2012, coming on as a substitute.

He appeared again as a substitute in a 4–1 victory over Aston Villa, winning a penalty for the fourth goal. On 22 December 2012, he made his first start in a 1–0 loss at home to Sunderland before being substituted after 55 minutes.

His only competitive goal for the club came in a 5–1 victory over Barnsley in the League Cup on 27 August 2013.

On 2 September 2013, Mayuka joined Ligue 1 side Sochaux on a season-long loan deal.

On 30 July 2015, manager Ronald Koeman confirmed that Mayuka ‘had no future at Southampton’, and he was removed from the first-team, having failed to score in any of his 16 league appearances for Southampton.

On 31 August 2015, Mayuka joined French club FC Metz of Ligue 2, signing a three-year deal.

On 15 January 2016, Mayuka joined Egyptian club Zamalek on three-and-a-half-year deal.

On 9 November 2017, Mayuka returned to Israel and joined Hapoel Ra’anana.

In April 2019, Mayuka took back to Zambia and joined Green Buffaloes.