Michael Traynor's hedge school in the Red Bay caves, and David Manson's pioneer “play-school” in Donegall Street in Belfast provided his early education.

In 1797 he co-founded the charitable Belfast Dispensary and Fever Hospital in Factory Row (typhus was a great scourge of the town and it was impossible to control the infection and nurse victims in their own homes).

[9] MacDonnell had supported Drennan and Tennent in the foundation of the non-denominational Academical Institution in 1810, and served the college variously as Visitor and Manager between for 1810 to 1837.

[4] In July 1792, MacDonnell helped organise the national harp festival in Belfast, arranged to coincide with the town's Bastille Day celebrations.

[13] Later in 1808, MacDonnell and his brother Alexander co-founded the Belfast Harp Society, endowing their former teacher Arthur O'Neill as its principal instructor.

[16] In 1830, with Neilson's former pupil at the Academical Institution, Robert Shipboy MacAdam, and with the patronage of the Arthur Hill, Marquess of Downshire, MacDonnell founded Cuideacht Gaoidhilge Uladh (the Ulster Gaelic Society).

The society, which was to remain active until 1843, abjured the commitment of other Protestants sharing its interest in the contemporary Irish vernacular to religious evangelism.

[18] At a Bastille Day town meeting in 1792, MacDonnell helped move an Irish Volunteer resolution approving Catholic Emancipation, which he linked it to the call for the abolition of slavery.

[19][20] Speaking on the same motion were friends who, following an address by Dublin barrister and Catholic Committee secretary Theobald Wolfe Tone, had joined together the previous October to form the Society of United Irishmen.

But MacDonnell had taken issue with Russell's militant republicanism, suggesting that, just as in their shared scientific interests, his judgement in politics was often rash and, in working "all from first principles", naïve.

[4] In a poem sketched for his sister Martha McTier, Epigraph-on the Living (October 1803), William Drennan decried "a man who could subscribe To hang that friend at Last Whom future history will describe The Brutus of Belfast.

[28] MacDonnell's later cooperation with William Drennan and other former United Irishmen in the foundation and management of the Academical Institution suggests that the bitterness was, in time, set aside.

[3] Conceding that time had "softened a little my feelings" Templeton met with MacDonnell in 1825, and shook hands,[29] a reconciliation possibly brokered by Mary Ann McCracken who ended her own embargo of the doctor.

Aodh Mac Domhnaill composed Tuireadh an Doctuir Mhic Domnhaill in his memory, and there is a plaque to MacDonnell near Murlough, County Antrim.