We explore the relationship between mid-infrared (mid-IR) and CO rotational line emission from massive star-forming galaxies, which is one of the tightest scalings in the local universe. We assemble a large set of unresolved and moderately (∼1 kpc) spatially resolved measurements of CO (1–0) and CO (2–1) intensity,
ICO, and mid-IR intensity, IMIR, at 8, 12, 22, and 24 μm. The ICO versus IMIR relationship is reasonably described by a power law with slopes 0.7–1.2 and normalization ICO ∼ 1 K km s−1 at IMIR ∼ 1 MJy sr−1. Both the slopes and intercepts vary systematically with choice of line and band. The comparison between the relations measured for CO (1–0) and CO (2–1) allow us to infer that μm and 12 μm bands, with strong polycyclic aromatic hydrocarbon (PAH) features, show steeper CO versus mid-IR slopes than the 22 and 24 μm, consistent with PAH emission arising not just from CO-bright gas but also from atomic or CO-dark gas. The CO-to-mid-IR ratio correlates with global galaxy stellar mass ( M⋆) and anticorrelates with star formation rate/ M⋆. At ∼1 kpc resolution, the first four PHANGS–JWST targets show CO-to-mid-IR relationships that are quantitatively similar to our larger literature sample, including showing the steep CO-to-mid-IR slopes for the JWST PAH-tracing bands, although we caution that these initial data have a small sample size and span a limited range of intensities.