Chronic obstructive pulmonary disease (COPD) is a serious respiratory disease with a rising incidence pattern. 5-aminolevulinic acid (5-ALA) has a potent anti-inflammatory effect, however, its impact on COPD has not been studied. Our aim is to investigate the involvement of AIM2/IL1α/Piezo1 signaling axis in the pathogenesis of COPD produced by LPS in rats, as well as the potential alleviating effect of 5-ALA, via AMPK activation, against this pathway. Forty male rats were specified into four groups: normal control; 5-ALA; LPS; LPS+5-ALA. Gene expressions of AMPK, Nrf2 and Piezo1 were examined using RT-PCR quantification. Furthermore, lung protein expression of AIM2 inflammosome was assessed by western blotting. HO-1 levels, in addition to other oxidative stress and inflammatory markers were also detected. Histopathological examination and immunostaining of inflammatory markers (NF-κB) were lastly determined. Our findings demonstrated that 5-ALA significantly upregulates AMPK, which in turn activating Nrf2/ Ho-1 axis with increased TAC levels and decreased ROS production. Through, 5-ALA prevented ROS overproduction, and subsequent AIM2/IL1α/Piezo1 signaling. Consequently, NF-κB activation and associated release of TNF-α and IL-6 were ultimately suppressed by 5-ALA. These results indicate that 5-ALA may possess a mitigating impact against inflammatory insult in COPD caused by LPS, via an AMPK-dependent mechanism, which is achieved by prohibiting AIM2/IL1α/Piezo1 pathway.