The tuber of Stephania rotunda is used to treat malaria in traditional medicine in many Asian countries. Cepharanthine is a bioactive bisbenzylisoquinoline alkaloid of the plant, in particular it presented antiplasmodial activity. Two modern and ecologic technologies were proposed to extract cepharanthine from S. rotunda tuber: ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE). Various parameters of these processes were studied to optimize the extraction of cepharanthine from the tuber. Quantification of cepharanthine was performed by a validated HPLC method. MAE in closed system, for 15 min, with the ratio solid–liquid 1/30, the solvent ethanol–water (50:50, v/v), at 80 °C and 100 W, was the most effective conditions on the extraction yield. UAE was the most ecologic because it did not need any heating and was shorter than MAE (10 min). Statistical analyses showed that these two methods exhibited the same efficiency for the extraction of cepharanthine and both methods were more efficient than percolation. MAE and UAE permitted the best extraction of cepharanthine from the S. rotunda tuber when the solvent used was ethanol–water in comparison with dichloromethane. Both eco-extractions, using ethanol–water, were found to be promising alternative methods for the extraction of cepharanthine from S. rotunda.