Lella and Massimo married in 1957 and together they established the Vignelli Office of Design and Architecture in Milan in 1960.
Lella then moved to Chicago and joined Skidmore, Owings & Merrill in 1959 as a junior designer in the Interiors department. In 1965, Massimo co-founded the Unimark International Corporation and Lella became the head of Unimark’s Interiors department a year later, in New York. In 1971, the Vignellis established Vignelli Associates, with Lella Vignelli as executive vice president, and Lella later served as chief executive officer. In 1978, the couple formed Vignelli Designs, a company dedicated to product and furniture design, of which Lella later became President.
Lella's work was widely featured in design publications in the United States and abroad. Examples of her and Massimo’s work have been included in the permanent collections of numerous museums, including the Museum of Modern Art, the Cooper-Hewitt Museum, the Metropolitan Museum of Art in New York, the Muses des Arts Decoratifs in Montreal, and Die Neue Sammlung in Munich. Exhibitions of Vignelli's work have been shown internationally. The major exhibit titled “Design:Vignelli” toured Europe between 1989 and 1993.