The importance of Mn2+ for pneumococcal physiology and virulence has been studied extensively. However, the specific cellular role(s) for which Mn2+ is required are yet to be fully elucidated. Here, we analyzed the effect of Mn2+ limitation on the transcriptome and proteome of Streptococcus pneumoniae D39. This was carried out by comparing a deletion mutant lacking the solute binding protein of the high-affinity Mn2+ transporter, pneumococcal surface antigen A (PsaA), with its isogenic wild-type counterpart. We provide clear evidence for the Mn2+-dependent regulation of the expression of oxidative-stress-response enzymes SpxB and Mn2+-SodA and virulence-associated genes pcpA and prtA. We also demonstrate the upregulation of at least one oxidative- and nitrosative-stress-response gene cluster, comprising adhC, nmlR, and czcD, in response to Mn2+ stress. A significant increase in 6-phosphogluconate dehydrogenase activity in the psaA mutant grown under Mn2+-replete conditions and upregulation of an oligopeptide ABC permease (AppDCBA) were also observed. Together, the results of transcriptomic and proteomic analyses provided evidence for Mn2+ having a central role in activating or stimulating enzymes involved in central carbon and general metabolism. Our results also highlight the importance of high-affinity Mn2+ transport by PsaA in pneumococcal competence, physiology, and metabolism and elucidate mechanisms underlying the response to Mn2+ stress.