A sarcoma is a type of cancer which is originated from the connective tissue cells. With the time, several sarcomas have become resistant to the current anti-tumoral drugs. Many works have been reported in order to explain some mechanisms of resistance in different types of sarcomas and around 2000 compounds have been tested as anti-sarcoma agents against several sarcoma cell lines. However, there is no an available methodology for the rational design of compounds with anti-sarcoma activity. The present work develops a unified fragment-based approach by employing a multi-target QSAR model for the efficient search and design of new anti-sarcoma agents against 12 sarcoma cell lines. The model was obtained with the use of a heterogeneous database of compounds and it was based on substructural descriptors. The percentages of correct classification of active and inactive compounds were higher than 85% in both cases. Also, the present approach provided the rapid extraction of substructural alerts responsible of anti-sarcoma profile by calculating the quantitative contributions of fragments to anti-sarcoma activity. To our knowledge, this is the first attempt to calculate the probabilities of anti-sarcoma activity of compounds against several sarcoma cell lines simultaneously, using a unified fragment-based QSAR model.