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<b>Background:</b> After its 2019 outbreak in Wuhan, scientists worldwide have been studying the epidemiology and clinical characteristics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in children. Evidence indicates that children with SARS-CoV-2 infection are more likely to develop upper and lower respiratory tract infections in association with other infectious agents, such as <i>Mycoplasma pneumoniae</i>. Here, we conducted a systematic review of SARS-CoV-2 and <i>Mycoplasma pneumoniae</i> co-infection and their clinical course in children. <b>Methods:</b> We evaluated the published literature on SARS-CoV-2 by using the medical databases PubMed, Embase, Cochrane Library, Scopus, and Web of Science. In the searches, the Medical Subject Heading (MeSH) terms “SARS-CoV-2 and <i>Mycoplasma pneumoniae</i>” AND “co-infection SARS-CoV-2” were used. Studies describing co-infection with SARS-CoV-2 and <i>Mycoplasma pneumoniae</i> in children were included in the review. The study was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. <b>Results:</b> According to the PRISMA guidelines, of the 38 identified studies, 14 were conducted in children (children/adolescents 0–18 years), 6 of which were included in this review. In total, 5867 children under the age of 17 years were diagnosed with SARS-CoV-2 infection through real-time polymerase chain reaction analysis of nasopharyngeal swabs to detect viral RNA. Elevated serum IgM levels specific to <i>Mycoplasma pneumoniae</i> were observed in 534 children and were associated with a Kawasaki-like illness in one child. To date, all of the children are alive. <b>Conclusion:</b> This study underlines the importance of considering, depending on the clinical context, a possible co-infection between SARS-CoV-2 and atypical bacteria, such as <i>Mycoplasma pneumoniae.</i> Co-infections with other respiratory pathogens during the pandemic and hospital stay can cause mistakes in clinical diagnostic and drug treatment. Physicians should perform early differential diagnosis of SARS-CoV-2 in association with other infectious agents. Further studies are needed to have a real incidence of these co-infections and their impact on symptoms, course, and outcome of patients with SARS-CoV-2.