Praxelis clematidea (Asteraceae) is a noxious invasive exotic plant in southern China, and it has caused great damage to ecological conditions and serious financial losses. In this study, four new phenolics (1, 2, 7, 8), and two new phenylpropanoids (3, 4), along with seventeen known compounds were separated and purified from the whole plant of P. clematidea. Their chemical structures were determined by extensive spectroscopic analysis methods. Additionally, the potential inhibitory activities on nitric oxide (NO) production and NF-κB nuclear translocation in LPS-triggered RAW 264.7 macrophages of the isolated compounds were evaluated. Notably, compounds 2, 7, and 8 showed significant inhibitory activities on NO production, and also inhibited the expression of iNOS and COX-2. Furthermore, compounds 2, 7, and 8 effectively suppressed the NF-κB nuclear translocation. These findings suggest that P. clematidea has the potential to be developed and promoted as a treatment for inflammation-related diseases.