Abstract Background Migraine is the most common neurological disorder and the second most disabling human condition. Autotaxin (ATX) is a plasma enzyme that leads to the formation of lysophosphatidic acid (LPA), which is involved in different functions involved in migraine, such as vascular tone control, inflammation, neuronal excitation, endothelial dysfunction, and neuropathic pain, among others. Most patients with migraine are females and, interestingly, ATX is physiologically higher in the serum of females compared to males. Objective As ATX may be a link between common mechanisms associated with migraine, we aimed to determine the potential role of ATX in migraine by studying its concentrations in serum between patients with episodic (EM) and chronic migraine (CM) compared to healthy controls, as well as the correlation of ATX with clinical outcomes, and other biomarkers described in migraine. Methods In this cross‐sectional study, healthy controls ( n = 62), and patients with EM ( n = 45), and CM ( n = 38) were studied. Clinical outcomes, such as migraine intensity as assessed on a visual analog scale (VAS), frequency of headaches (days/month), evolution time (months), and the duration of attacks (h) were investigated together with the serum biomarkers for inflammation (interleukin 6 [IL‐6] and IL‐10), trigeminovascular system activation (calcitonin gene‐related peptide [CGRP]), endothelial dysfunction (pentraxin 3 [PTX3], cellular fibrinogen [cFN], soluble tumor necrosis factor‐like weak inducer of apoptosis [sTWEAK]), and ATX. Additionally, the serum lipidomic biomarkers profile was also analyzed. Results Serum ATX levels were found to be significantly elevated in both patients with EM (mean [standard deviation, SD] 310.7 [79.7] ng/mL) and CM (mean [SD] 336.7 [66.9] ng/mL) compared to controls (mean [SD] 212.3 [53.2] ng/mL) ( p < 0.001). Elevated ATX levels were associated with migraine outcomes in CM, such as VAS score (Spearman's coefficient = 0.405, p < 0.05), frequency (Spearman's coefficient = 0.718, p < 0.001), and evolution time (Spearman's coefficient = 0.2257, p < 0.01). ATX was correlated with CGRP (Pearson's coefficient = 0.278, p < 0.001), PTX3 (Pearson's coefficient = 0.468, p < 0.001), sTWEAK (Pearson's coefficient = 0.242, p < 0.001), cFN (Pearson's coefficient = 0.252, p < 0.01), and IL‐6 serum levels (Pearson's coefficient = 0.159, p < 0.001). A drastic decrease in serum lysophosphatidylcholine levels indicates high ATX activity in patients with migraine. Conclusions Serum levels of ATX were significantly increased in patients with EM and CM. In addition, ATX correlates with clinical outcomes, as well as CGRP, endothelial dysfunction and inflammation biomarkers. Further studies are necessary to elucidate the potential role of ATX as a therapeutic target for migraine.