Cadmium (Cd) is one of the most toxic environmental pollutants affecting the growth and reproduction of various plants. Analysis of the biological adaptation and tolerance mechanisms of the hyperaccumulator Erigeron annuus to Cd stress may help identify new plant species for phytoremediation and in optimizing the process. This study is to the first to analyze the molecular composition and diversity of dissolved organic matter (DOM) secreted by roots using FT-ICR MS, and multiple physiological and biochemical indexes of E. annuus seedlings grown in solutions containing 0–200 Cd μmol L−1. The results showed that E. annuus had strong photosynthetic adaptation and protection ability under Cd stress. Cd was immobilized or compartmentalized by cell walls and vacuoles in the plant, thus alleviating Cd stress. Activation of anti-oxidation defense mechanisms also played an important role in alleviating or eliminating Cd toxicity in E. annuus. High Cd stress promoted production of a higher proportion of new molecules in DOM secreted by E. annuus roots compared to low Cd stress. DOM secreted by roots contributed to plant resistance to Cd-induced stress via producing more carbohydrates, aromatic structures and tannins. Results indicate the mechanisms underpinning the potential use of E. annuus as a phytoremediator in environments with moderate Cd pollution.