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Abstract Over the past decade, several millimeter interferometer programs have mapped the nearby star-forming galaxy M51 at a spatial resolution of ≤170 pc. This study combines observations from three major programs: the PdBI Arcsecond Whirlpool Survey, the SMA M51 large program, and the Surveying the Whirlpool at Arcseconds with NOEMA. The data set includes the (1–0) and (2–1) rotational transitions of¹²CO,¹³CO, and C¹⁸O isotopologues. The observations cover ther< 3 kpc region, including the center and part of the disk, thereby ensuring strong detections of the weaker¹³CO and C¹⁸O lines. All observations are convolved in this analysis to an angular resolution of 4″, corresponding to a physical scale of 170 pc. We investigate empirical line ratio relations and quantitatively evaluate molecular gas conditions such as temperature, density, and the CO-to-H₂conversion factor (α_CO). We employ two approaches to study the molecular gas conditions: (i) assuming local thermodynamic equilibrium (LTE) to analytically determine the CO column density andα_CO, and (ii) using non-LTE modeling withRADEXto fit physical conditions to observed CO isotopologue intensities. We find that theα_COvalues in the center and along the inner spiral arm are ∼0.5 dex (LTE) and 0.1 dex (non-LTE) below the Milky Way inner disk value. The average non-LTEα_COis 2.4 ± 0.5M_⊙pc⁻²(K km s⁻¹)⁻¹. While both methods show dispersion due to underlying assumptions, the scatter is larger for LTE-derived values. This study underscores the necessity for robust CO line modeling to accurately constrain the molecular interstellar medium’s physical and chemical conditions in nearby galaxies.