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Because of the high mortality rate and limited antifungal therapy options, there is an urgent need to understand the impact of dynamic processes between fungal pathogens and hosts that influence cryptococcal pathogenesis and disease outcomes. With known common limitations in human studies, experimental murine cryptococcosis models that can recapitulate human disease provide a valuable tool for studying fungal virulence and the host interaction, leading to development of better treatment strategies. Infection with <jats:italic>Cryptococcus<\/jats:italic> in mice via intranasal inhalation is mostly used because it is noninvasive and considered to be the most common mode of infection, strongly correlating with cryptococcal disease in humans. The protocols described in this article provide the procedures of establishing a murine model of <jats:italic>Cryptococcus<\/jats:italic> infection by intranasal inhalation and assessing the host immune response and disease progression during <jats:italic>Cryptococcus<\/jats:italic> infection. \u00a9 2024 Wiley Periodicals LLC.<\/jats:p><jats:p><jats:bold>Basic Protocol 1<\/jats:bold>: Murine model of pulmonary cryptococcal infection via intranasal inhalation<\/jats:p><jats:p><jats:bold>Basic Protocol 2<\/jats:bold>: Assessment of the pulmonary immune response during <jats:italic>Cryptococcus<\/jats:italic> infection<\/jats:p><jats:p><jats:bold>Support Protocol<\/jats:bold>: Evaluation of pulmonary gene expression by real\u2010time PCR<\/jats:p><jats:p><jats:bold>Basic Protocol 3<\/jats:bold>: Enumeration of survival rate and organ fungal 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