In traditional Congolese medicine, the plants Crassocephalum montuosum (CrasMon) and Crassocephalum picridifolium (CrasPic) are used to treat bacterial gastroenteritis. In the present study, the antibacterial and antioxidant activities as well as the acute and subacute toxicity of organic extracts from the whole plant of the two investigated taxa were evaluated. Physicochemical parameters were also determined, and total phenolics, flavonoids, and tannins were investigated and assayed. The antibacterial and antioxidant activities of the plant extracts were evaluated using disc diffusion, tube macrodilution, and DPPH tests. Conversely, traditional solution reactions, gravimetric tests, and spectrophotometric tests were used to generate physicochemical profiles, identify secondary metabolite groups, and perform microdilution and DPPH tests to evaluate the antibacterial and antioxidant activities, respectively. OECD tests were adapted to assess the acute and subacute toxicity. All the extracts showed antibacterial activity against E. coli and S. typhi strains with the diameter zone of inhibition (DZI) ranging from 12 to 23 mm and the minimum inhibitory concentration (MIC): 15.625–125 μg·mL−1. The methanolic extract of CrasPic showed the most pronounced activity with a DZI of 21–23 mm and MIC of 15.625–62.5 μg·mL−1. All extracts showed high antioxidant activity with IC50 (half maximal inhibitory concentration) ranging from 11.6 to 21.8 μg·mL−1, with the methanolic extract of CrasMon showing the most pronounced activity. Both plants contain a variety of phytochemicals including coumarins, quinones, flavonoids, phenols, saponins, tannins, and terpenoids. The methanolic extract of CrasPic exhibits the highest content of total phenolics (300 mg·GAE·g−1), flavonoids (56 mg·QE·g−1), and tannins (155 mg·GAE·g−1). These extracts have a median lethal dose (LD50) > 5000 mg·kg−1 and no signs of toxicity at 200 mg·kg−1 after 30 days of oral administration to Cavia porcellus. The total ash content was determined to be 14.2% and 15.8% (on a dry weight basis), with the ash insoluble in hydrochloric acid exhibiting a range of 4.04%–5.03%. CrasMon and CrasPic have been demonstrated to exhibit a good antibacterial and antioxidant activities, at least in part, due to the presence of phenolic compounds. These activities may provide a rationale for their use in traditional Congolese medicine against gastroenteritis.