To investigate the effects of cadmium (Cd) on photosynthetic and antioxidant activities of safflower (Carthamus tinctorius L.) plants, two cultivars (Yuming and New safflower No. 4) were used for long-term pot experiment, under 0, 25, 50 or 100 mg Cd kg−1 (DW) soil conditions. The results showed that there is a large amount of Cd (148.6–277.2 mg kg−1) accumulated in the shoot of safflower, indicating this species might be a potential Cd accumulator. Exposure to 25–100 mg Cd kg−1 soil decreased the net photosynthetic rate by 25.6%–48.9% for New safflower No. 4, and 16.7%–57.3% for Yuming, respectively. The inhibition of photosynthesis might result from the limitation of stomatal conductance, reduction in photosynthetic pigment, and destruction of photosynthetic apparatus caused by Cd stress. Cd caused an enhancement of malondialdehyde (MDA), an increase in activity of superoxide dismutase (SOD) and ascorbate peroxidase (APX), and a decrease in catalase (CAT) activity for both cultivars. It seems that SOD and APX accounted for the scavenging of oxidant stress in safflower cultivars. The physiological response of safflower plants to Cd stress was cultivar- and dose- dependent. New safflower No. 4 exhibited high photosynthetic performance at high Cd stress, which may be contributed by high intercellular CO2 concentration, APX activity and Car/Chl ratio. In contrast, Yuming is more tolerant to Cd toxicity at low Cd level, in which an efficient antioxidant system is involved.