Born in Targovishte, Isa started playing football at PFC Svetkavitsa's youth teams.

[2] Ismail Isa made his unofficial debut for Levski in a friendly match against Dynamo Kyiv on 20 January 2008.

On 21 July, he was sent off at the stroke of half time for a second bookable offense in the return leg against the Andorran side, but despite playing a man down his team won 5–0.

Isa scored his first goal for Levski in the Bulgarian A Professional Football Group on 23 August 2010 against Kaliakra Kavarna.

[4] On 22 October 2011, Isa made his official debut for his new team, playing the first 85 minutes and earning himself a yellow card in the 2:0 home win over Istanbul B.B.

[6] He marked his debut by scoring a goal in the 2:0 win over FC Tiraspol in a Moldovan Super Cup match that was held on 29 June.

On 7 February 2015, Isa made his first appearance for Bulgaria, in the 0–0 draw against Romania in a non-official friendly match, playing over the course of the first 70 minutes.

[9] He was recalled to the national team in May 2019 by new manager Krasimir Balakov and played as a starter in the 1–2 away loss against the Czech Republic in a Euro 2020 qualifier on 7 June 2019, opening the scoring with his first international goal.