(1) Background: An important concomitant of stroke is neuroinflammation. Pomalido-mide, a clinically available immunomodulatory imide drug (IMiD) used in cancer therapy, lowers TNF‐α generation and thus has potent anti‐inflammatory actions. Well‐tolerated analogs may pro-vide a stroke treatment and allow evaluation of the role of neuroinflammation in the ischemic brain. (2) Methods: Two novel pomalidomide derivatives, 3,6′‐dithiopomalidomide (3,6′‐DP) and 1,6′‐di-thiopomalidomide (1,6′‐DP), were evaluated alongside pomalidomide in a rat middle cerebral artery occlusion (MCAo) stroke model, and their anti‐inflammatory actions were characterized. (3) Results: Post‐MCAo administration of all drugs lowered pro‐inflammatory TNF‐α and IL1‐β levels, and reduced stroke‐induced postural asymmetry and infarct size. Whereas 3,6′‐ and 1,6′‐DP, like pomalidomide, potently bound to cereblon in cellular studies, 3,6′‐DP did not lower Ikaros, Aiolos or SALL4 levels—critical intermediates mediating the anticancer/teratogenic actions of pomalido-mide and IMiDs. 3,6′‐DP and 1,6′‐DP lacked activity in mammalian chromosome aberration, AMES and hERG channel assays –critical FDA regulatory tests. Finally, 3,6′‐ and 1,6′‐DP mitigated inflammation across rat primary dopaminergic neuron and microglia mixed cultures challenged with α‐ synuclein and mouse LPS‐challenged RAW 264.7 cells. (4) Conclusion: Neuroinflammation mediated via TNF‐α plays a key role in stroke outcome, and 3,6′‐DP and 1,6′‐DP may prove valuable as stroke therapies and thus warrant further preclinical development.