Background: Mycoplasma pneumoniae pneumonia (MPP) is often complicated with co-infections that worsen the prognosis, but the outcomes in pediatric cases are unclear. The aim of this study is to investigate the association of co-infection and outcomes in severe MPP that occurs in childhood. Methods: This retrospective study included 184 pediatric cases of severe MPP that were managed at our hospital (between January 2014 and December 2017). The cohort was divided into the single Mycoplasma pneumoniae infection, co-infection with a noxa other than M. pneumoniae, and co-infection with two or more noxae other than M. pneumoniae groups. The demographic and clinical information of the patients was compared via statistical analysis. Results: The incidence of co-infections was high at 64.1%. Cytomegalovirus and Epstein-Barr virus were the most common causes of co-infection. According to the findings of binary logistic regression analysis, the presence of more than one pathogen (other than M. pneumoniae) was positively associated with the score determined from Pediatric Risk of Mortality III (β = 0.760, odds ratio [OR] = 2.139, 95% confidence interval [CI] = 1.391–2.390, P = 0.001), Pediatric Critical Illness Score (β = 1.203, OR = 3.328, 95% CI = 1.723–6.731, P = 0.000), and total length of hospital stay (β = 0.730, OR = 2.075, 95% CI = 1.404–3.066, P = 0.000). Conclusion: Viral and bacterial co-infection in pediatric cases of severe MPP is positively associated with hospitalization period and disease severity, and ultimately, may increase the chances of severe illness and death among children.