In addition to their intended use, progesterone (P4)-based contraceptives promote anti-inflammatory immune responses, yet their effects on the outcome of infectious diseases, including influenza A virus (IAV) infection, are rarely evaluated. To evaluate their impact on immune responses to sequential IAV infections, adult female mice were treated with placebo or one of two progestins, P4 or levonorgestrel (LNG), and infected with a mouse-adapted H1N1 (maH1N1) virus. Treatment with P4 or LNG reduced morbidity but had no effect on pulmonary virus titers during primary H1N1 infection compared to placebo treatment. In serum and bronchoalveolar lavage fluid, total anti-IAV IgG and IgA titers and virus-neutralizing antibody titers but not hemagglutinin stalk antibody titers were lower in progestin-treated mice than placebo-treated mice. Females were challenged 6 weeks later with either an maH1N1 drift variant (maH1N1dv) or maH3N2 IAV. The level of protection following infection with the maH1N1dv was similar among all groups. In contrast, following challenge with maH3N2, progestin treatment reduced survival as well as the numbers and activity of H1N1- and H3N2-specific memory CD8 T cells, including tissue-resident cells, compared with placebo treatment. In contrast to primary IAV infection, progestin treatment increased the titers of neutralizing and IgG antibodies against both challenge viruses compared with those achieved with placebo treatment. While the immunomodulatory properties of progestins protected immunologically naive female mice from the severe outcomes from IAV infection, it made them more susceptible to secondary challenge with a heterologous IAV, despite improving their antibody responses against a secondary IAV infection. Taken together, the immunomodulatory effects of progestins differentially regulate the outcome of infection depending on exposure history. The impact of hormone-based contraceptives on the outcome of infectious diseases outside the reproductive tract is rarely considered. Using a mouse model, we have made the novel observation that treatment with either progesterone or a synthetic analog found in hormonal contraceptives, levonorgestrel, impacts sequential influenza A virus infection by modulating antibody responses and decreasing the numbers and activity of memory CD8 T cells. Progestins reduced the antibody responses during primary H1N1 virus infection but increased antibody titers following a sequential infection with either an H1N1 drift variant or an H3N2 virus. Following challenge with an H3N2 virus, female mice treated with progestins experienced greater mortality with increased pulmonary inflammation and reduced numbers and activity of CD8 T cells. This study suggests that progestins significantly affect adaptive immune responses to influenza A virus infection, with their effect on the outcome of infection depending on exposure history.