This retrospective case control study compared serum total thyroxine (tT4) concentrations in hospitalized critical cats (CCs) and non-hospitalized cats with non-thyroidal chronic diseases (chronic group, CG) and evaluated the relationship between the serum tT4 concentration of CCs and systemic inflammation (systemic inflammatory response syndrome (SIRS)), disease severity (Acute Patient Physiologic and Laboratory Evaluation (APPLEfast)), and prognosis. Cats with previously suspected or diagnosed thyroid disease were excluded. Serum tT4 was evaluated in surplus serum samples at the time of admission for CCs and CGs. The APPLEfast score of the CC group was calculated at admission. The systemic inflammatory response syndrome (SIRS) in CCs was determined using proposed criteria. Cats were divided into survivors and non-survivors according to the discharge outcome. Forty-nine cats were retrospectively included. Twenty-seven cats died during hospitalization. The CG group was composed of 37 cats. The CC group showed a significantly lower tT4 compared to the CG group (1.3 ± 0.7 vs. 2 ± 0.9; p < 0.0001). Among SIRS, APPLEfast, and tT4, only tT4 was associated with mortality (p = 0.04). The tT4 cut-off point for mortality was 1.65 μg/dL (sensitivity 81%, specificity 57%, odds ratio (OR) 5.6). Twenty-five cats (51%) had SIRS that was not associated with tT4. Non-thyroidal illness syndrome can occur in critically ill cats and the evaluation of tT4 in hospitalized cats could add prognostic information.