Lisa Scottoline is joyful and light, seated in her bright home office outside Philadelphia on a chilly December afternoon. Blond hair pools on her shoulders to frame her often-smiling face. The spitfire’s lip gloss shines through the Zoom screen.

Her youthful energy belies her 65 years, but it has fueled her prolific and accomplished writing career. The bestselling author of 33 novels is known for fast-paced thrillers and humorous essays, which have had commercial success and received critical acclaim. Her storytelling has been described as gripping, propulsive, and unforgettable.

It took all of Scottoline’s formidable talent and experience to write her latest novel, Eternal (Putnam, Mar.), which marks a departure for her in nearly every way. Named after the Eternal City of Rome, her first work of historical fiction takes place during the ventennio—the 20 years of Fascist rule under Mussolini beginning in the 1920s. While her previous novels unfurl over a few days, Eternal spans two decades. And instead of taking three months to draft her typical story’s 90,000 words, she spent a year and a half writing this book—all 160,000 words of it.

It’s a sweeping epic about the love triangle between three best friends from different backgrounds. It covers themes of family, justice, and love, as Scottoline’s books long have. But this saga delves deeper—into loyalty and loss, family and food, love and hate. It unfolds in one of the world’s most beautiful cities at a time of darkness and despair.

The bold Elisabetta D’Orfeo is a beautiful, aspiring novelist from Trastevere. Marco Terrizzi is the youngest, athletic son of a professional cycling family from Tiber Island. And Sandro Simone is a mathematics prodigy and son of a lawyer and doctor who hail from the city’s Jewish ghetto. Both Sandro and Marco fall in love with Elisabetta. Their lives unfold in the shadow of World War II as the Nazis upend the laws of Rome and threaten their families, their homes, and their friendship.

Scottoline’s own story begins in Philadelphia, where she and her brother grew up in a warm Italian American family led by their feisty matriarch, Mother Mary, the youngest of 19 children. “I grew up with lots and lots of aunts at my house all the time when we were young,” Scottoline recalls. “I remember so many big, wet kisses and moles that were vaguely scratchy.”

Scottoline studied English (graduating magna cum laude in just three years) at the University of Pennsylvania. There, she attended a yearlong seminar taught by the late, great American novelist Philip Roth. One semester covered the literature of the Holocaust. Mr. Roth, as he asked students to address him, introduced Scottoline to the work of Primo Levi, an Italian Jewish chemist sent to Auschwitz during WWII. His memoir, Survival in Auschwitz, was important beyond measure. Not only was he among the most gifted writers the world had ever seen, Roth told them, but the Italian Holocaust was scarcely understood—and it ought to be.

Scottoline agreed, and she knew then that she wanted to change that, one day. But first, she’d go on to study law at Penn. As a girl, episodes of Perry Mason showed her a clear way to wrangle justice. “I wanted to fight for the underdog, and I actually felt that I did,” she says. She clerked for state and federal appellate court judges before becoming a litigator. “I had the luxury of trying cases I thought were right and fighting cases we thought were wrong. I loved it. But I never really identified with my profession. I saw litigation in novelistic terms: good versus bad, who’s right and who’s wrong. You look at a particular set of facts, and you marshal them.”

After her daughter was born and Scottoline divorced, she left the law firm and quietly started writing. Her secret was short-lived. Her first novel, Everywhere That Mary Went, earned a nomination for an Edgar Award for best paperback original, and her second, Final Appeal, won the Edgar in the same category. Since then, she has served as president of the Mystery Writers of America and received dozens of other awards. Her books have been translated into 30 languages, and she has 30 million copies in print in the United States. She has built her success with practice: writing 2,000 words a day, every single day.

For the past 12 years, Scottoline has also cowritten the hilarious and wry “Chick Wit” column with her daughter, Francesca Serritella, for the Philadelphia Inquirer. (It has since been adapted into a series of nonfiction books.) Crafting those 800-word columns, Scottoline says, has not only been fun—it’s also been a great exercise. “They’ve taught me to get to the point sooner,” she adds.

In Eternal, the first sentence of the prologue does just that. “You meet this woman, and you know it’s a love triangle,” Scottoline says. “She’s made a choice and had a baby with somebody. You have to ask, ‘Who did she have her baby with, and why is she telling the story now?’ ”

To find out, Scottoline spent every day and most nights reading, writing, and watching Italian movies and documentaries on the History channel. “I probably bought 300 books, and I took thousands of pictures and 40 videos for this book,” she says. She even bought the same cherry red 1930 Olivetti typewriter Elisabetta uses. “I steep myself in this 24/7, so what comes out will be perfectly synthesized. I tell writers, ‘You have to protect your flame, your little candle.’ Don’t let distractions blow it out.”

Writing about history demands accuracy. And the voices of characters living a century ago must sound authentic, if we’re to believe—and care about—them. For her research, Scottoline asked a historian to give her a tour of Rome’s Jewish quarter, home of one of the oldest continuous Jewish communities in Western civilization.

“I remember when we came to the Arch of Titus, I said, ‘God, that’s beautiful,’ ” Scottoline recalls. But her guide told her flatly that it isn’t. When she asked him why, he explained that the Jews were brought to ancient Rome as slaves. (One relief shows Titus’s triumphant conquest of Jerusalem in 71 CE.) “He told me, ‘When I see that arch, I see a yoke around the neck of a human being.’ I realized then that that’s how my character will see this, too.”

An epic may be big, but it has to be human, too. The angst a teenage girl feels about getting her first bra is as real as bigger questions, such as that of what one is allowed to want. After ruthless revisions, Scottoline felt every word left truly mattered. Her editor, Mark Tavani, loved the story, but suggested it was too long. “He called me late one night and said, ‘I think you should start on page 171,’ ” Scottoline recalls. “He was so right.”

With a laugh, Tavani says the process reminded him of Michelangelo. “He said the sculpture is already complete within every marble block. You just have to keep carving until it reveals itself.”

It took a few rounds to pare down all of the excess—so readers can discover the magic inside for themselves. “Lisa is the truest natural-born storyteller,” Tavani says. “She’s so good at it because she understands how people listen.”

For Tavani, an editor’s greatest honor is having a chance to work on the book an author was born to write. He says Eternal is that book. He hopes, and trusts, that Scottoline’s loyal following and new readers alike will sense the passion coursing through it.

The heft of a long, successful career can burden any writer. Critics expect certain stories, told in familiar ways. It’s the job of a storyteller with a devoted readership to deliver. But Scottoline had to believe that her fans would will follow her on this journey.

“I say it all the time: ‘Little Lisa, be not afraid. Little Lisa, give it a go,’ ” she says. “I think all of us writers are in a room cheering ourselves on. Whether you’ve published 30 books or no books, it’s always the same: there’s a blank page and a challenge, and you need to meet it. I knew this story needed to be told. I told myself, ‘This is what you’ve always wanted. It’s the culmination of your career.’ ”

Victoria Scanlan Stefanakos has written for Forbes, Newsweek, and Working Mother.