Exocytosis of lysosomes from macrophages has been described as a response to microbial cytotoxins and haemolysins, as well as for releasing pro‐inflammatory cytokines interleukin (IL)‐1β and IL‐18 during inflammasome activation. The mycobacterial ESX‐1 secretion system, encoded in part by the Region of Difference‐1, is a virulence factor necessary for phagosome escape and host cell lysis by a contact‐dependent haemolysin in Mycobacterium marinum. Here we show that ESX‐1 from M. marinum and M. tuberculosis is required for Ca²⁺‐dependent induction of lysosome secretion from macrophages. Mycobacteria‐induced lysosome secretion was concurrent to release of IL‐1β and IL‐18, dependent on phagocytosis of bacteria containing ESX‐1. Synthesis but not release of IL‐1β and IL‐18 occurred in response to dead bacilli and bacteria lacking ESX‐1, indicating that only cytokine release was regulated by ESX‐1. Release of these cytokines and exocytosis of lysosomes were independent of intracellular mycobacterial growth, yet correlated with mycobacteria‐encoded haemolytic activity, demonstrating a parallel pathway for the two responses. We further identified inflammasome components caspase‐1, ASC and NALP3, but not Ipaf, required for release of IL‐1β and IL‐18. Collectively, these results reveal a role for ESX‐1 in triggering secretion of lysosomes, as well as release of IL‐1β and IL‐18 during mycobacteria infection.