The present paper aims to analyze the pathogen spectrum of hand, foot and mouth disease (HFMD) and epidemic dynamics of main pathogens in Shanghai from 2011 to 2016. The samples were collected from children diagnosed with HFMD in sentinel hospitals from 2011 to 2016. General and classified tests for enteroviruses were carried out, and the biological characteristics of both recombined and non-recombined coxsackievirus A6 (CA6) strains were analyzed. It was found that the main pathogens of HFMD were enterovirus type 71 (EV71) and CA16 from 2011 to 2012 in Shanghai area, and CA6 became the main pathogen in the autumn of 2012. From 2013 to 2014, recombined CA6 (R CA6) occupied a certain proportion, but non-recombined CA6 (NR CA6) became dominant during 2015—2016. R CA6 and NR CA6 were highly proliferative in human rhabdomyoma cells (RD cells) but had no obvious proliferation in human oral epidermoid carcinoma cells (KB cells), human embryo lung cells (MRC-5 cells) and human laryngeal epidermoid carcinoma cells (HEp-2 cells). The results confirmed that CA6 was the major causative agent of HFMD in Shanghai in recent years. Both R CA6 and NR CA6 strains could infect RD cells. The detection ratio of R CA6 and NR CA6 changed year by year. These results indicate that monitoring and characterizing the main pathogens of HFMD continuously was a critical step for the prevention of HFMD and vaccine development.