Background Antimicrobial resistance (AMR) poses a significant challenge for treating pneumococcal disease. This study assessed AMR trends in Streptococcus pneumoniae from US children. Methods We evaluated antibiotic resistance, defined as facility antimicrobial susceptibility reports of intermediate/resistant, in 30-day non-duplicate S. pneumoniae isolates from children (<18 years) with invasive (blood or cerebrospinal fluid/neurological) or non-invasive (respiratory or ear/nose/throat) isolates at 219 US hospital inpatient/outpatient settings in the BD Insights Research Database (January 2011-February 2020). We used descriptive statistics to characterize the percentage of AMR isolates and generalized estimated equations to assess variations in resistance over time. Results Of 7,605 S. pneumoniae isolates analyzed, 6,641 (87.3%) were from non-invasive sources. Resistance rates were higher in non-invasive versus invasive isolates. Isolates showed high observed rates of resistance to ≥1 drug class (56.8%), ≥2 drug classes (30.7%), macrolides (39.9%), and penicillin (39.6%) and significant annual increases in resistance to ≥1 drug class (+0.9%), ≥2 drug classes (+1.8%), and macrolides (+5.0%). Conclusions Among US children over the last decade, S. pneumoniae isolates showed persistently high rates of resistance to antibiotics and significant increases in ≥1 drug class, ≥2 drug classes, and macrolide resistance rates. Efforts to address AMR in S. pneumoniae may require vaccines targeting resistant serotypes and antimicrobial stewardship efforts.