Systems and methods for hydroprocessing a heavy oil feedstock, the system employs a plurality of contacting zones and separation zones and a solvent deasphalting (SDA) unit for providing at least a portion of the heavy oil feedstock. The contacting zones operate under hydrocracking conditions, employing a slurry catalyst for upgrading the deasphalted oil, forming upgraded products of lower boiling hydrocarbons. In the separation zones which operates at a temperature within 20° F. and a pressure within 10 psi of the pressure in the contacting zones, upgraded products are removed overhead and optionally, further treated in an in-line hydrotreater.