Lord Vetinari was born into the extremely powerful Vetinari family (a word play on the real life family of the Medici and on the word "veterinary") and raised by his aunt, Lady Roberta Meserole.

As a youth, he enrolled in the Assassins' Guild which, apart from teaching its students how to kill other people for money, also gives them an excellent education. Lord Vetinari was particularly interested in the classical arts and (in flagrant defiance of the Guild's conventions of style) camouflage, though he was failed in his stealth examination (because of his apparent absence in class.) Because of the similarity of his name to "veterinary", he endured the nickname of Dog-botherer. Vetinari graduated from the Guild with exceptional marks, with disconcertingly high marks in attention to detail.

In his late teens, Vetinari was involved in the Glorious 25th of May (Night Watch), to which his most notable contribution was the non-assassination of the then-Patrician of Ankh-Morpork, Homicidal Lord Winder at a crowded party. Vetinari was present at Winder's death, but although certainly intending to assassinate Winder, Vetinari's mere arrival was enough to cause Winder to die of fright, possibly following a heart attack. Vetinari was able to drop his weapon beside Winder's corpse without using it, and leave - all seemingly unobserved by anyone in the room bar Winder (although it was hinted that the party was arranged for the very occasion of Winder's assassination). Vetinari showed up in full Assassin regalia, which Winder thought was something out of a nightmare. Later, he fought alongside the remnants of John Keel's Night Watch against the remnants of The Cable Street Particulars, (Colloquially known as The Unmentionables), the late Lord Winder's secret police.

He later journeyed to Überwald on what is known as the Grand Sneer (a parody of Grand Tour); travels of the younger members of rich families to backward areas to see at first hand how inferior they are. There he met the vampire Lady Margolotta. It is implied that the two had some kind of relationship, and stated more clearly that he taught her a lot of what she knows.

Lord Vetinari succeeded Mad Lord Snapcase, who had been as mad as the name suggests. One of Vetinari's earliest actions and a sample of his way of running the city was to legalize Guilds such as those of the Thieves and the "Seamstresses", which had been active but outlawed for years. Their leaders became esteemed members of society and their members insured and licensed. Vetinari also made it clear to them that he knew everything about them, right down to where their wives had their hair done and their children played. Therefore, the Guilds did what he asked of them, and eventually, lawlessness was not eliminated so much as organized. Nowadays, for a modest fee, an Ankh-Morpork citizen may walk the streets confident that he will not be mugged more than a few times per year and will always receive a receipt.

Lord Vetinari's genius political thinking and his running of the city can be summed up by his belief that what people wish for most is not good government, or even justice, but merely for things to stay the same; the Vetinari family motto is, after all, Si non confectus, non reficiat (If it ain't broke, don't fix it). This does not mean that there are absolutely no changes, however; things that don't work are fixed very quickly, even if it does not look like they are at first.

Despite being technically a dictator, Lord Vetinari does not exercise the despotic rule that characterised some of his predecessors. He is, in fact, the archetype of a benevolent dictator, in a chilly, inscrutable way. In The Truth, he permits the emergence of a free press, and has rarely, if ever, been known to drag innocent people off to dungeons without trial. The dungeons of the palace held a number of felons imprisoned "at his lordship's pleasure", and since Lord Vetinari was seldom very pleased they were generally in for the long haul. The notable exception to this rule are mimes, who Vetinari despises for some unknown reason. Vetinari banned all mime performances from Ankh-Morpork shortly after taking power. Mimes who violate the ban usually find themselves trying to climb invisible ladders out of Vetinari's scorpion pit whilst reading a sign saying 'learn the words.'

Morporkians are, however, in no doubt that Vetinari is firmly in charge of the city; the political system of Ankh-Morpork is described as "One Man, One Vote", in which Vetinari is the Man, and he has the Vote. In Going Postal, he first appears to avoid meddling in the affairs of private business, but suddenly exercises his executive power in closing several prominent banks for audit at the end of the novel. (While Vetinari could have ordered an investigation of the Clacks company and their financial endeavors at any time, it is worth noting that he did not do so until public opinion allowed it – only then did he proclaim his right as a "tyrant" to launch such an inquiry.) Vetinari is broadly tolerant of individual rights, but highly intolerant of people who place their own interests above those of the city.

While he is just as unpopular as those that came before him, Lord Vetinari is disturbingly sane and still alive- unlike his predecessors. He has achieved this by ensuring that even though all power-wielding groups in the city dislike him, they dislike each other more. He also carefully arranges matters so that a reality which includes him as Patrician is slightly better than one which does not. The Assassins' Guild no longer accepts contracts on the Patrician – he is the only person besides Samuel Vimes to have been taken off the register. He had the highest official price ever: $1 Million Ankh-Morpork Dollars (Feet of Clay).

In Thud!, his rule of the city is likened to a room full of tension, with people bickering and shouting at one another, and "in the middle of it all, one man quietly doing his own thing". Other reasons for the Patrician's continued rule is his mastery of diplomacy and manipulation of human nature, his distant and menacing air, his everpresent calmness and composure which makes other people ill at ease, his abilities as a listener (often people tell him things simply to fill his silence) and of course his very, very good skills as an Assassin ("Mr. Slant had failed to tell the New Firm about a number of things, and one of them was that Vetinari moved like a snake" (The Truth)).

Vetinari has created (or at least continued) the use of a team of clerks who bring him information on just about everything; they serve, among other functions, as accountants, forensic auditors, and a domestic intelligence service. The apparent head (or at least one of those seen to most frequently liaise with Vetinari) of this team is Drumknott.

Several attempts have been made on Vetinari's life or position. Shortly after his ascent to office, he was briefly turned into a lizard by a wizard under the influence of a Sourcerer. He was deposed for a time in favour of a summoned dragon and locked up in his own dungeons, from which he escaped at his leisure (Guards! Guards!) – the door to his cell was very large and heavy, and was absolutely covered in bars, bolts and locks. On the inside. All that was on the outside was a single lock, the key to which Vetinari had hidden in the cell (he has two mottos a ruler should remember when building dungeons: "never build a dungeon you wouldn't want to spend the night in yourself" and "never build a dungeon you can't get out of"). He was shot in the leg with a gonne (sic) and now walks with an ebony cane, though only in public (Men at Arms). A year later, he was poisoned with arsenic (Feet of Clay).

During the brief war with Klatch, Vetinari surrendered unconditionally, resulting in his near-exile. However, when the island which was the cause of controversy sank into the ocean (again), all the terms of surrender were off and the Klatchian leader lost face, which was Vetinari's plan all along. The result of which is that Vetinari was congratulated instead of being deposed and exiled (Jingo).

Some time later, Vetinari was framed for assault and theft from the city treasury. Again he came a hair's breadth from deposition (The Truth). He was arrested by his own Commander of the Watch (Samuel Vimes) for attempted murder, and spent part of the book incarcerated, though (as shown in Guards! Guards!) imprisonment isn't a burden if you're able to control the means of said imprisonment.

None of these events – even poisoning – seem to have fazed him at all. There have also been numerous attempts on his life by Assassins retained by other parties; the universal failure of these attempts led to the Guild's refusal to accept further bounties on Vetinari's death.