Medicinal plants have been employed as an alternative method to treat diabetes. One is Cissus sicyoides, a plant from the Amazon region (Northern Brazil), which is morphologically similar to Wedelia paludosa, a plant easily found in Southern Brazil. Thus, this study aimed to assess the potential toxicity of C. sicyoides and W. paludosa’s leaves water extracts. Through phytochemical screening, phenolic compounds and alkaloids were observed in both species and coumarins only W. paludosa’s aqueous extract. Phenolic compounds were quantified in both extracts and C. sicyoides presented 1.36 ± 0.04 mg/pyrogalic acid equivalent (PAE), whereas W. paludosa presented 3.27 ± 0.07 mg/PAE. Total antioxidant power was measured by the ferric reduction assay. Cissus sicyoides exhibited total antioxidant activity of 748.0 ± 104.5 μM and W. paludosa, 1971.5 ± 141.0 μM. Cissus sicyoides showed an inhibition rate for the alpha-glucosidases enzyme assay of 55.2 ± 1.7% and W. paludosa, 85.8 ± 9.7%. The formation of reactive oxygen species was evaluated by the DCFH-DA method, its formation being higher in W. paludosa’s water extracts than in C. sicyoides. Cell viability was evaluated by the Sulforhodamine B and MTT assays. Wedelia paludosa’s extracts’ exposure presented a cell viability close to positive control starting from 2 mg/mL to 30 mg/mL, whereas C. sicyoides demonstrated statistical significant low viability at the highest concentration when compared with the negative control. Moreover, cell death mechanism was investigated, having W. paludosa’s extract indicated death by necrosis. The results suggest low toxicity for C. sicyoides’ extract and high toxicity for W. paludosa’s extract.