Neuroinflammation characterizes multiple neurologic diseases, including primary inflammatory conditions such as multiple sclerosis and classical neurodegenerative diseases. Aberrant activation of the innate immune system contributes to disease progression, but drugs modulating innate immunity, particularly within the central nervous system (CNS), are lacking. The CNS-penetrant natural product bryostatin-1 attenuates neuroinflammation by targeting innate myeloid cells. Supplies of natural bryostatin-1 are limited, but a recent scalable good manufacturing practice (GMP) synthesis has enabled access to it and its analogs (bryologs), the latter providing a path to more efficacious, better tolerated, and more accessible agents. Here, we show that multiple synthetically accessible bryologs replicate the anti-inflammatory effects of bryostatin-1 on innate immune cells in vitro, and a lead bryolog attenuates neuroinflammation in vivo, actions mechanistically dependent on protein kinase C (PKC) binding. Our findings identify bryologs as promising drug candidates for targeting innate immunity in neuroinflammation and create a platform for evaluation of synthetic PKC modulators in neuroinflammatory diseases.