(1) Background: Anaphylaxis is a rapid-onset, life-threatening hypersensitivity reaction. This study explores the epidemiological trends and clinical outcomes of adult patients with and without asthma hospitalized for anaphylaxis in Spain from 2016 to 2021. (2) Methods: Data from the Spanish National Hospital Discharge Database (RAE-CMBD) were analyzed. We stratified patients with anaphylaxis based on their asthma diagnosis and evaluated various comorbidities and clinical outcomes. Propensity score matching was used to match confounders. (3) Results: The total number of hospitalizations for anaphylaxis remained stable, with a decrease in 2020 probably due to the COVID-19 pandemic. Drug-induced anaphylaxis increased, in addition to being the main triggering factor. Asthma prevalence among those admitted for anaphylaxis emerged from 7.63% to 10.69%, with a higher frequency of respiratory failure and need for mechanical ventilation in this group; despite this, ICU admissions and in-hospital mortality did not differ significantly between asthmatics and non-asthmatics. Asthma was also not a risk factor for severe anaphylaxis. Multivariable analysis identified advanced age, ischemic heart disease, acute respiratory failure, and invasive mechanical ventilation as factors associated with severe anaphylaxis. (4) Conclusions: This study provides valuable information on the complexity of anaphylaxis, its relationship with asthma, and factors influencing its severity. Overall, clinical outcomes did not differ significantly in asthmatic patients compared to non-asthmatic patients, although asthmatic patients had more respiratory complications. Further research is necessary to delve deeper into the multifactorial nature of anaphylaxis and its implications in clinical practice.