This paper presents a systematic method for dealing with mobility analysis and structural synthesis of a class of important spatial mechanisms with coupling chains, which involve more complex coupling relations than spatial parallel mechanisms. First, an approach to the establishment of the motion screw equation of the class of mechanisms is derived. Then, a general methodology for mobility analysis along with detection of rigid substructures is proposed based on the motion screw equation. Third, the principle of structural synthesis of the class of mechanisms is established on the basis of the method of mobility analysis. Finally, some novel spatial mechanisms with coupling chains are synthesized, illustrating the effectiveness of the method. The study of the paper will benefit structural analysis and synthesis of more complex spatial mechanisms with coupling chains.