The investigation of heavy metal wastewater treatment utilizing microalgae adsorption has been extensively demonstrated. However, the response mechanism based on metabolomics to analyze the time-series changes of microalgae under Cd stress has not been described in detail. In this study, SEM/TEM demonstrated that Cd accumulated on the cell surface of microalgae and was bioconcentrated in the cytoplasm, vesicles, and chloroplasts. Carbonyl/quinone/ketone/carboxyl groups (OCO), membrane polysaccharides (OH), and phospholipids (PO) were involved in the interaction of Cd ions, and the chlorophyll content underwent a process of decreasing in the early stage (1.62 mg/g at 48 h) and recovering to the normal level in the late stage, and the contents of MDA, GSH, and SOD were all increased (29.7 nmol/g, 0.23 mg/g, and 30.01 u/106 cells) and then gradually returned to the steady state. The results of EPS content and fluorescent labeling showed that Cd induced the overexpression and synthesis of extracellular polysaccharides and proteins, which is one of the defense mechanisms participating in the reduction of cellular damage by complexed Cd. Metabolomics results indicated that the malate synthesis pathway was activated after Cd-20 h, and the microalgal cells began to shift the metabolic pathway to storage lipid or polysaccharide biosynthesis. In the Calvin cycle, the expression of D-Sedoheptulose 7-phosphate in Cd-20 h_vs_ck and Cd-72 h_vs_Cd-20 h firstly declined and then increased, and the photosynthesis system was suppressed at the beginning, and then gradually returned to normal to maintain the successful development of the dark reaction. The results of time series analysis revealed that the response of microalgae to Cd was categorized into fast response and slow response to regulate cell adsorption and growth metabolism.