"We see it right here in Mississippi how swiftly progress can hurtle backward," Michelle said at the Jackson State University on Saturday.
"How easy it is to single out a small group and marginalise them because of who they are or who they love."
Mississippi is under growing criticism from human rights groups and businesses over a controversial law passed on April 5 restricting the rights of the LGBT - lesbian, gay, bisexual, transgender - community.
Under the law, religious organisations will be able to deny LGBT people marriage, adoption and foster care services, fire or refuse to employ them, and decline to rent or sell them property.
Medical professionals will be permitted to refuse to participate in treatments, counselling and surgery related to "sex reassignment or gender identity transitioning".
"So we've got to stand side by side with all our neighbours -- straight, gay, lesbian, bisexual, transgender; Muslim, Jew, Christian, Hindu immigrant, Native American -- because the march for civil rights isn't just about African Americans, it's about all Americans," she said.
In her speech, the first lady also reflected on the heated political battles her husband had endured as president and urged students not to fall into disarray over the "anger and vitriol" in the political environment.
"We pay endless attention to folks who are blocking action, blocking judges, blocking immigration, blocking a raise in the minimum wage. Just blocking," Obama said.
"We are consumed with the anger and vitriol that are bubbling up, with folks shouting at each other, using hateful and divisive language."
Michelle also spoke about criticism directed towards her husband over his eight years as president, including jibes made by Republican frontrunner Donald Trump.(IANS)