Streptococcus pneumoniae isolates from the United States (n = 1038; 2019-2021) were susceptible to omadacycline (99.8%), levofloxacin (99.7%), and ceftriaxone (98.1%), whereas doxycycline (80.2%), oral penicillin (63.5%), cefpodoxime (76.8%), and azithromycin (54.4%) activity was limited. Tet (M) did not affect omadacycline activity but altered activity of older tetracyclines including doxycycline, suggesting omadacycline is an important option for treatment of community-acquired bacterial pneumonia.