Nadine Menendez “kept him in the dark” on financial matters, the politician’s attorney, Avi Weitzman, told the jury.
But prosecutor Lara Pomerantz said Mr Menendez, 70, used his wife as a go-between in trading political influence for money, gifts and gold bars.
The long-serving New Jersey Democrat “put his power up for sale”, she said.
Mr Menendez is accused of accepting bribes, including gold bars and a Mercedes-Benz convertible, in exchange for helping foreign governments. He has pleaded not guilty to all charges.
The trial, in a Manhattan federal court, could stretch to July. Mr Menendez is required to attend each day.
He was the top-ranking Democrat on the powerful Senate Foreign Relations Committee for more than five years, which gave him sway over US foreign policy. He was removed as chairman after he was charged.
He married Nadine Menendez, who was born in Lebanon before moving to the US as a child, in 2020. She is being tried separately on her own bribery and corruption charges, to which she has pleaded not guilty.
Laying out the government’s case against Mr Menendez, Ms Pomerantz took aim at what she described as a “betrayal” of the senator’s oath of office.
“This was not politics as usual. This was politics for profit. This was a United States senator on the take,” she said.
And, Ms Pomerantz said, the Democrat used his wife to help facilitate the deals. Mr Menendez was “too smart” to send texts and emails regarding the bribes himself, she alleged, so he advised his spouse on what to do.
Mr Menendez’s defence team painted a different picture of the senator’s marriage, portraying Mrs Menendez as a financially troubled individual who left her husband out of her scramble to resolve money problems and “to get cash and assets any way she could”.
Prosecutors alleged Mr Menendez’s wife, Nadine, acted as a “go-between” in the bribery scheme
“Let me say this about Nadine: Nadine had financial concerns that she kept from Bob,” said the defence attorney.
They led separate lives, Mr Weitzman said, with Mr Menendez often focused on helping his constituents from his seat in Washington.
“The government’s allegations that the senator sold his office and his loyalty to this country are outrageously false,” Mr Weitzman said. “Bob was doing his job, and he was doing it right.”
Wednesday’s opening arguments followed more than two days of jury selection. Twelve jurors and six alternatives were ultimately chosen, a group that includes an investment banker, a doctor and some therapists.
Mr Menendez has been charged with 18 criminal counts, including bribery, extortion, wire fraud, obstruction of justice and acting as a foreign agent.
Investigators executing a search warrant at his home in September found more than $480,000 (£380,000) in cash stuffed in envelopes and coats, and 13 gold bars worth over $100,000.
Agents also found other apparent gifts, including a Mercedes-Benz and a range of home furnishings.
Prosecutors say the items discovered were part of a scheme to aid the government of Egypt. They also allege Mr Menendez accepted bribes to use his influence to benefit Qatar.
Mr Menendez is on trial with Fred Daibes, a New Jersey real estate developer who allegedly delivered the gold and cash to the senator, and businessman Wael Hana, who allegedly brokered a deal between Mr Menendez and the Egyptian government. Both Mr Daibes and Mr Hana have also pleaded not guilty.
By Brandon Drenon & Holly Honderich, BBC News
