AbstractA combination of partial least squares (PLS) regression and design of experiments was used to analyse and define the short‐ and long‐term loss mechanisms of carvacrol from polymer/clay nanocomposite films used as an antimicrobial food packaging material. Three formulation x variables were evaluated: type of nanoclay, concentration of nanoclay and concentration of compatibilizer agent. Five experimental y responses were measured: loss of carvacrol from the films stored at room conditions on the third and fifth days (short‐term loss); on the forty‐fifth and sixtieth days (long‐term loss); and the polymer/clay level of intercalation. All variables and responses were simultaneously calibrated by an ANOVA‐validated (P < 0.05) comprehensive PLS interaction model with a satisfactory R2 = 0.956 and Q2 = 0.505. A differentiation and discrimination of the mechanisms that control the loss of carvacrol over different periods of time was observed. Short‐term loss seems to be controlled mainly by direct molecular interactions in the interlayer space between carvacrol and the nanoclay organomodifier. Long‐term loss seems to be mainly controlled by diffusion within the nanocomposite matrix once carvacrol has left the nanoclay interlayer space, and it is closely related to the levels of intercalation reached in the nanocomposite. © 2016 Society of Chemical Industry