Subacute thyroiditis (SAT) represents an inflammatory disease of the thyroid gland, often resulting from viral infections or post-viral inflammatory responses. Long-term hypothyroidism is a possible evolution, requiring frequent follow-up and, if necessary, levothyroxine (LT4) replacement therapy. We retrospectively included 139 patients (out of 428) with SAT referring to the “Fondazione Policlinico Universitario A. Gemelli IRCCS” (Rome), between 2010 and 2022 to identify predictive parameters for long-term hypothyroidism. We evaluated TSH, FT4, and FT3 at four timepoints (diagnosis, 4–8 weeks, 10–20 weeks, and 28–54 weeks). We started LT4 therapy in patients with TSH > 10 μUI/mL or between 4–10 μUI/mL, with symptoms of hypothyroidism. “Long-term hypothyroidism” was defined as TSH > 4 μUI/mL after LT4 reduction and/or withdrawal. Univariate analysis showed correlations between long-term hypothyroidism and higher FT3 and FT4 and positive anti-Tg Abs at diagnosis and higher changes in TSH values (ΔTSH), decreased thyroid volume, and persistence of hypoechoic areas during follow-up. Furthermore, more severe thyrotoxicosis at presentation may be associated with a faster progression to hypothyroidism, likely due to greater thyroid damage. Multivariable analysis found ΔTSH (TP2-TP1) as an independent predictor of hypothyroidism. We propose specific biochemical and ultrasonographic parameters at diagnosis and during follow-up as possible predictors of long-term hypothyroidism after SAT, reducing treatment and healthcare costs for most patients who will never require replacement therapy.